Body Fluid Biomarkers of Neurological Injury in HIV-1-Associated Neurocognitive Disorder

Abstract

Since combined antiretroviral therapy for human immunodeficiency virus-associated neurocognitive dysfunction (HAND) only slows the disease’s progression, early identification and timely intervention are crucial for effective therapy. In this article, we review the latest evidence in body fluid biomarkers of HAND, providing an overview of research conducted on cerebrospinal fluid and blood samples to draw conclusions on promising biomarkers. Although the significance of biomarkers such as amyloid metabolites, tau proteins, neurofilament light chain, myelin oligodendrocyte glycoprotein, and brain-derived neurotrophic factor in the early detection of HAND may not be immediately clear, they could potentially play a crucial role in evaluating prognosis and tracking the effectiveness of treatment.

Introduction

The introduction of combined antiretroviral therapy (cART) in 1996 marked a significant turning point in the history of human immunodeficiency virus (HIV), which substantially extended the lifespan of people living with HIV.¹ Since then, HIV has shifted from a terminal illness to a chronic condition.² Despite the efficacy of cART, the virus persists in hidden reservoirs, which may lead to cognitive and motor function decline, as well as changes in behavior and mood as patients age, resulting in a condition known as HIV-associated neurocognitive dysfunction (HAND).^3,4

HAND is diagnosed by functional assessment, neuropsychological assessment, and observation of clinical symptoms.⁵ However, many health care facilities face limitations in neuropsychological resources, and several screening tests are not easily feasible to implement in outpatient settings. Challenges such as time constraints, budgetary limitations, and specific patient demographics may influence diagnostic decision-making in certain regions. Consequently, these obstacles could hinder the prompt and accurate diagnosis for people living with HIV.

While neuropsychological testing remains the gold standard for diagnosing HAND, it is often time-consuming and costly, particularly in resource-limited settings. Early screening and diagnosis of HAND are crucial for health and quality of life, necessitating accessible biomarkers and cost-effective screening tests. These measures could help slow the progression from asymptomatic neurocognitive impairment (ANI) disorder and mild neurocognitive disorder (MND) to HIV-associated dementia (HAD). Researchers are seeking new biomarkers for timely diagnosis of HAND. Various neurological injury biomarkers in cerebrospinal fluid (CSF) and blood have been investigated, but their consistent correlation with HAND remains unclear. Here, we review the five biomarkers, including soluble amyloid precursor proteins (sAPPα and sAPPβ), β-amyloid (Aβ) 40 and 42, total and phosphorylated tau (t-tau and p-tau), neurofilament light chain (NFL), myelin oligodendrocyte glycoprotein (MOG), and brain-derived neurotrophic factor (BDNF). This review aims to synthesize existing data to identify key body fluid biomarkers of neurological injury in HAND and provide a systematic review of relevant research.

Diagnostic Criteria of HAND

HAND, previously known as HIV encephalopathy or acquired immunodeficiency syndrome dementia complex (ADC), is classified based on the “Frascati criteria,” which categorizes it into three levels of severity: ANI, MND, and HAD. Nevertheless, the classification is only applicable in cases where neurocognitive impairment cannot be explained by other factors. Recent studies indicate that the false positive rate of this criterion surpasses 20%.⁶ Consequently, some researchers have proposed a new diagnostic framework for HAND.⁶ The key distinctions between Frascati criteria and the new framework involve two aspects. First, HAND is defined as any cognitive impairment in people living with HIV rather than being directly caused by the virus. Second, clinical diagnosis primarily relies on medical history rather than cognitive evaluation tests. There remains controversy regarding whether HAND is caused directly by the virus or indirectly through neuroinflammation or other mechanisms. Current research on viral replication is largely limited to measuring nucleic acids in CSF, which provides only an approximate estimate of viral titers in the brain.⁷ It is unable to track the real state of the patient’s brain tissue.

In the era of successful application of cART and the aging of the people living with HIV, cognitive impairment in this group is often multifactorial.⁸ However, cognitive test results for people living with HIV who are suspected to have cognitive impairment vary widely based on socioeconomic status and educational backgrounds.⁹ Currently, available diagnostic tools or methods lack the sensitivity and specificity required for accurate HAND diagnosis.¹⁰ The lack of accurate diagnosis of HAND may hinder the identification of biomarkers associated with neuropathogenesis.¹¹

Body Fluid Biomarkers

Despite antiretroviral therapy increasing life expectancy for people living with HIV, the rate of HAND remains steady, affecting up to 50% of patients.^12,13 Soon after HIV acquisition, the virus enters the central nervous system (CNS) via monocytes and predominantly spreads to intraparenchymal mononuclear phagocytes and astrocytes.¹⁴ The CNS can serve as a reservoir for latent HIV acquisition.¹⁵ Prolonged HIV presence can stimulate neuroinflammation, ultimately resulting in neuronal degeneration and damage.¹⁶

Unique biomarkers are crucial for the rapid and accurate diagnosis of HAND, especially in distinguishing MND from ANI. Identifying unique biomarkers can not only assist researchers in recognizing shared disease pathogenesis mechanisms but also inspire novel treatment approaches.

Given the challenge in diagnosing this condition without neuropsychological assessments, it is imperative to discover additional biomarkers for monitoring progression and recovery posttreatment. Currently, specific biomarkers for HAND are primarily identified in blood and CSF.

Current Status of HAND Body Fluid Biomarkers of Neurological Injury

HAND develops slowly and progresses gradually, making diagnosis challenging due to its subtle initial clinical manifestations among people living with HIV. This often leads to delayed identification and intervention. In people living with HIV receiving cART therapy, various complex factors, such as gender, age, drug abuse, and inflammation resulting from concomitant infections, lead to a complex link between HIV replication in the CNS and the development of HAND.¹⁷ Given the progressive and incurable nature of HAND, early screening promotion has the potential to enhance outcomes and enhance the well-being and longevity of the affected population.

Numerous ongoing studies are exploring potential body fluid biomarkers of HAND to aid in assessing disease progression, developing treatments, and monitoring treatment responses. Currently, there is no ideal body fluid biomarker for HAND, with primary sample sources including CSF and blood (serum and plasma). Although the examination of CSF is considered invasive, it remains the most accurate method for assessing the biochemical reactions associated with CNS diseases. Previous research on surrogate biomarkers for HAND has primarily focused on biomarkers related to inflammation, immune response, oxidative stress, vascular function, lipid metabolism, and neurological damage. Among these, inflammatory biomarkers have been extensively studied. While the specific inflammatory biomarkers that can reliably predict the development of HAND remain unclear, they provide valuable insight into the underlying mechanisms of the disease. Nevertheless, there has been limited investigation into the correlation between HAND and biomarkers of neurological damage in bodily fluids.

Some studies indicate that CSF biomarkers can detect ongoing damage in people living with HIV and predict the progression of subclinical neuropathology and the subsequent development of HAND. The existing evidence presents conflicting findings regarding biomarkers of neurological damage in HAND.^18

–21 Conversely, other studies have suggested that biomarkers such as NFL, tau, and APP are more indicative of later stages of the HAND progression.^22
–24

Biomarkers of Neurological Injury in HAND

Amyloid metabolites (sAPPα, sAPPβ, Aβ, Aβ40, and Aβ 42)

sAPPα and sAPPβ

The transmembrane protein APP is predominantly expressed in the brain, where it undergoes rapid and complex metabolic processes involving various proteases. APP plays a role in processes such as axonal growth, dendrite formation, and neuronal migration.^25,26 Its expression is widespread in neurons, and its proteolytic cleavage by secretases generates metabolites known to contribute to various neuropathological conditions.²⁷ APP can be cleaved by either α-secretase or β-secretase, leading to the release of sAPPβ and sAPPα from the cell surface. In the context of amyloidogenic processing, γ-secretase cleaves C99 to produce Aβ peptides of varying lengths.

Robust evidence has revealed that the accumulation of intraneuronal amyloid or perivascular diffuse amyloid depositions is a characteristic of HAND.²⁸ This amyloid buildup is most commonly observed in the hippocampus and frontal lobe, particularly within pyramidal neurons and along axonal pathways in people living with HIV.²⁹ Meanwhile, an analysis of the frontal and temporal lobe amyloid plaques in 97 participants dying at ages 30–69 years revealed an increase in amyloid plaques in the brains of people living with HIV.³⁰ Decreased levels of CSF sAPPα and sAPPβ have been reported in cases of HAD and HIV-related CNS opportunistic infections.¹⁹ The simultaneous decline in CSF sAPPα and sAPPβ in ADC and CNS opportunistic infections implies a potential impact of CNS immune activation or inflammation on the production or breakdown of neuronal amyloid.¹⁹ HAD has been linked to reduced CSF sAPPα and sAPPβ,²² supporting earlier findings that revealed decreased levels of these APP cleavage products in people with HAD. These findings suggest that amyloid is affected in HIV-associated brain injury and may have clinical applications in certain settings. However, Gemma et al.³¹ have shown that brain amyloid burden does not differ between virally suppressed people with HAND and cognitively normal older controls on a group level. While the study does not present statistical proof of a general increase in amyloid in people living with HIV and HAND, it underscores the significance of individual differences among people with chronic HIV and HAND.

Aβ, Aβ 40, and Aβ 42

Under normal circumstances, the generation and clearance of Aβ in brain tissue maintain a dynamic balance. An increase in Aβ generation coupled with a decrease in its clearance leads to excessive accumulation, resulting in the formation of senile plaques that have neurotoxic effects, damaging synapses, altering neurotransmitter secretion, and causing neuronal death—key contributors to Alzheimer’s disease (AD).³² Aβ proteins are generated through the proteolysis of APP along either the amyloidogenic or nonamyloidogenic pathway.³³ The primary amino acid sequence of Aβ was initially identified from extracellular deposits and amyloid plaques in 1984.³⁴ Aβ monomers aggregate into three distinct forms: oligomers, protofibrils, and amyloid fibrils. Larger and insoluble, amyloid fibrils can assemble into plaques, whereas soluble amyloid oligomers may spread throughout the brain. The mechanisms by which Aβ exerts its toxicity on neurons have been extensively studied. Aβ directly interacts with cell membranes via charged lipids, inducing oxidative stress^35
–37 and activating astrocytes and microglia, which can lead to neuronal death.³⁸ Excess Aβ promotes the aggregate formation of amyloid plaques in the extracellular space, causing synaptic deficits and intracellular calcium disruption.^39,40 HIV-1 viral proteins have been shown to potentially impact Aβ synthesis and clearance mechanisms.^41

–44 There are two potential pathways: first, HIV-1 transactivator of transcription and envelope glycoprotein gp120 may increase Aβ synthesis, secretion, and accumulation.^41,43 Second, tat and/or tat-derived peptides could inhibit neprilysin, a key enzyme for Aβ degradation.^45

–48

People living with HIV have increased deposition of Aβ plaques in the brain.^30,49 Notably, Li and colleagues³³ reported the presence of intraneuronal Aβ buildup in the frontal cortex and hippocampus of both HIV-1 transgenic rats (aged over 12 months) and people with HAND, suggesting a potential link to synaptodendritic damage related to HIV-1. Furthermore, a study from the University of California⁴² analyzed the levels and distribution of Aβ immunoreactivity in the frontal cortex of people living with HIV through autopsy. The study showed that compared with controls without HIV, people living with HIV exhibited abundant intracellular Aβ immunostaining in pyramidal neurons and along axonal tracts. In particular, people with HIV encephalitis (HIVE) showed significantly higher levels of intraneuronal Aβ immunoreactivity compared with those having HIV but not HIVE. These indicate that chronic HIV acquisition may disrupt the clearance of proteins such as Aβ, exacerbating neuronal damage and cognitive impairment in this population.

sAPPβ, Aβ40, and Aβ42 serve as soluble indicators of amyloidogenic processing of APP. α-secretase cleaves APP between Aβ regions, inhibiting the production of Aβ40/42 and releasing sAPPα into the interstitial fluid and CSF.²² Aβ peptides can be further broken down into Aβ 40 and Aβ 42.^50,51 While Aβ 40 is the most prevalent subtype in the brain,⁴⁹ Aβ 42 predominates in neural plaques.^52,53 Sun et al. propose that the accumulation of Aβ in neurons could hinder memory either through direct toxicity, disruption of synaptic plasticity, or the spread of Aβ via neuron-derived exosomes.⁵⁴ Research reveals that HIV-1 promotes the release of extracellular vesicles from brain endothelial cells, leading to an increase in the Aβ content of these vesicles. Furthermore, extracellular vesicles have the ability to transfer Aβ to other cells in the neurovascular unit, such as astrocytes and pericytes. These processes may play a role in the excessive buildup of amyloid in the brains of people living with HIV, potentially contributing to the development of neurocognitive impairment.⁵⁵ However, some studies found that cognitive impairment in people living with HIV was associated with decreased levels of CSF Aβ42, indicating possible amyloid deposition in the brain rather than just neuron death.^56
–58 Further consideration of the reasons for low CSF Aβ42 in HAND may require ongoing research.

The integrity of the blood–brain barrier (BBB) is crucial for the regulation of Aβ levels and plays a role in the accumulation of Aβ in the brain. A study demonstrates that the level of Aβ42 in the CSF is elevated in people living with HIV who have compromised BBB function.⁵⁹

Mothapo and colleagues⁶⁰ analyzed CSF and plasma samples from 32 participants, including 22 people living with HIV and 10 controls without HIV, finding a tendency for higher levels of plasma Aβ-42 to be detected more frequently in people with HIV-associated cognitive deficits compared with HIV normal cognitive function and controls without HIV. This result may be related to the small sample size, which has hampered statistical analysis. The change of Aβ concentration in blood circulation is interfered with by many factors. Therefore, the extent to which circulating Aβ42 truly reflects the differences between people with and without HAND remains questionable.

Tau proteins

Tau, a key microtubule-associated protein in mature neurons, plays a crucial role in microtubule structure and stability.⁶¹ In healthy individuals, tau proteins are primarily found in neurons (where they stabilize microtubules and maintain dynamic equilibrium), with only a small amount of tau proteins present in nonneuronal cells.⁶¹ It is predominantly expressed in nonmyelinated cortical axons. Hyperphosphorylated tau is typically absent in younger, healthy individuals,⁶² and while most brains exhibit some hyperphosphorylated tau by age,⁶³ postmortem examinations of exceptionally aged, healthy individuals reveal minimal tau pathology.⁶⁴ Therefore, the accumulation of tau may not be an inevitable consequence of aging.

A study shows that injecting lipopolysaccharide, a typical inflammatory agent, into the brains of mice modified by the APP gene has further elucidated that inflammatory stimuli can facilitate tau phosphorylation.⁶⁵ Elevated t-tau levels signify cortical axonal degeneration, whereas increased p-tau concentrations in CSF signal abnormal tau hyperphosphorylation, resulting in axonal instability and potential aggregation into neurofibrillary tangles, a defining feature of AD and other tau-related disorders.^66,67

The study by Anthony and colleagues did show that tau protein in the brains of people living with HIV accelerated deposition both before and after the introduction of highly active antiretroviral therapy (HAART),⁶⁸ and increased levels of hyperphosphorylated tau were noted in the hippocampus of people living with HIV.⁶⁸ In a prospectively followed neurocognitive assessment autopsy study of 135 people living with HIV, Gonzalez et al. used immunohistochemistry to assess neuronal p-tau in medial temporal and lateral frontal lobes. Their result suggests that the accumulation of neuronal p-tau contributes to memory impairments in middle-aged people living with HIV.⁶⁹ Patrick et al.⁷⁰ observed increased expression of cyclin-dependent kinase 5 in the brains of 43 people with HIVE (autopsy) and in gp120 Tg mice (animal model), leading to neurotoxicity through the promotion of abnormal tau phosphorylation.

Clifford et al.,⁵⁷ in contrast to Brew’s study, found that people living with HIV and HAND did not exhibit characteristic CSF levels of t-tau and p-tau associated with AD. Jan et al.⁷¹ also reported no elevation in CSF p-tau in people with HAD in one of their studies. Another study showed that reduced CSF phosphorylated tau at threonine 181 (p-Tau181) levels was seen in association with HAND.⁷² It is well known that reductions in CSF Aβ42 are a reliable indicator of amyloid deposition in people with AD.^57,73
–75 Interestingly, normal to slightly lower levels of CSF tau and p-tau181 measurements were able to distinguish people with HAND from AD.⁵⁷ These evidences suggest that specific tau species in CSF could aid in distinguishing between HIV-associated cognitive decline and AD.⁵⁷ Guha’s results⁵⁸ support this notion. Elderly people living with HIV face an increased risk of developing amnestic mild cognitive impairment (aMCI) and AD. Biomarkers such as Aβ and tau are linked with aMCI/AD. Guha and colleagues⁵⁸ presented evidence suggesting that mild forms of HAND are associated with decreased levels of Aβ42 in CSF extracellular vesicles and an elevated CSF extracellular vesicle Tau/Aβ42 ratio. These findings could potentially help in differentiating aMCI/AD from HIV-related cognitive disorders in older people living with HIV in future research. Given the aging people living with HIV, this differentiation could become increasingly vital.

Similar to NFL, elevated CSF t-tau indicates neuronal injury, although it is less sensitive than NFL. p-tau is an unvalidated surrogate marker of brain aging and may not be a useful indicator of neurological aging in HIV, as it also increases with normal aging.

NFL

Neurofilament (NF) is an intermediate filament specific to neurons, consisting of four subunits (NFL, NF medium, NF heavy chain, and α-internexin).⁶³ They are highly present in dendrites, neuronal cell bodies, and axons, playing critical roles in structural support, transport, and nerve transmission.⁷⁶ The release of NF into the interstitial fluid occurs with the destruction of the axon membrane. Among the four subunits, NFL is the most abundant and soluble, making it the most easily measurable NF component in biological fluids.⁶³ NFL, a 68 kDa class IV intermediate filament protein encoded by the NFL gene on chromosome 8 (8p21.2), is the predominant intermediate filament protein in neurons.^77,78 As the light subunit of the NF protein, NFL is a key structural element of myelinated axons. NFL protein is primarily enriched in the axons of neurons. Additionally, it may be released in large quantities from damaged axons into the CSF and blood, leading to elevated levels of NFL in both CSF and blood. Therefore, elevated levels of NFL in CSF or blood are often used as potential biomarkers for axonal damage and neuronal death.⁷⁹ However, the changes of NFL protein in CSF are not specific. The concentration of NFL in CSF might increase in normal elderly people.⁸⁰ This change has also been observed in other neurodegenerative diseases, such as AD.⁸¹

Although not specific to any disease, NFL can be valuable in assessing the presence and extent of ongoing CNS injury in HIV acquisition. Compared with controls without HIV, people living with HIV showed a significant increase in the concentrations of NFL in CSF and blood.^82,83 NFL levels are notably elevated in people with HAD and untreated neuroasymptomatics with low CD4 counts.^21,82 A separate study discovered that CSF NFL levels were elevated in mild HAND compared with those who were neurocognitively normal.⁸⁴ In more studies, NFL is sensitive to CNS damage related to HIV acquisition.^20,21,23,85 In a study evaluating various stages of HIV acquisition, CSF NFL emerged as the most sensitive neuronal marker among multiple targets tested.²² Another investigation, involving a retrospective cross-sectional analysis of 48 people living with HIV among different levels of cognitive impairment and no antiretroviral therapy, exhibited a significant positive correlation between CSF NFL levels and plasma HIV RNA viral load, as well as a negative correlation with plasma CD4⁺ T-lymphocyte count. This indicates a potential connection between neuronal injury and systemic HIV acquisition.⁸⁶ Gisslén et al.²⁰ retrospectively identified nine participants taking part in a longitudinal cohort study who developed ADC and had undergone a lumbar puncture within 2 years prior to presentation. Elevated CSF NFL concentrations were observed in 78% of the nine participants who later developed ADC.

CSF NFL may prove to be a useful predictive marker for ADC. CSF NFL could potentially serve as a valuable marker for monitoring CNS injury in HIV acquisition and assessing the CNS efficacy of antiretroviral therapy.⁸⁷ Abdulle et al.²³ demonstrated that the concentrations of NFL were significantly elevated in people living with HIV who had no CNS opportunistic infections or tumors. These elevated NFL levels were associated with ADC and correlated with the severity of the condition.

Furthermore, NFL levels decreased with the initiation of cART and increased upon discontinuation of cART. In addition, Mellgren et al.¹⁸ also have observed that HAART appears to stop the progression of neurodegeneration in people living with HIV, as evidenced by the notable decrease in CSF NFL following the commencement of treatment in their research. The study by Anderson et al.⁸³ has illustrated a negative correlation between blood NFL and neuropsychological function in people living with HIV, with levels declining upon the commencement of antiretroviral therapy. Within a small subset of people living with HIV who were monitored longitudinally post-cART initiation, there was a significant reduction in plasma NFL levels aligning with the observed decrease in CSF NFL post-cART initiation. An analysis conducted in a key population has indicated that plasma NFL can be accurately quantified in people living with HIV and is strongly linked to CSF NFL levels.⁸² The findings of Natalia et al.⁸⁸ support the idea that blood NFL holds promise as a biomarker for cognitive impairment in people living with HIV who experience HAND.

MOG

MOG, which is exclusively expressed in oligodendrocytes, is a type I transmembrane protein present exclusively in the CNS and is of relatively low abundance.⁸⁹ A recent study reported three people with HIV who had MOG antibodies and were simultaneously afflicted with other CNS conditions, such as acute disseminated encephalomyelitis, transverse myelitis, and bilateral optic neuritis. All people living with HIV tested positive for MOG antibodies. These instances demonstrate the complexities in diagnosing and managing MOG-associated diseases in the context of advanced HIV status, where the risk of CNS opportunistic infections remains high even in the absence of immunosuppression. The study underscores the gaps in our understanding of the pathophysiology of MOG-associated diseases that require further investigation.⁹⁰

Limited data exist on the relationship between HAND and MOG. To date, only one study has examined anti-MOG antibodies in the context of HAND.⁹¹ This cross-sectional cohort study is the first to evaluate the potential of MOG antibodies in the CSF and serum of people living with HIV as indicators of disease progression and response to antiviral treatment.

The study revealed that anti-MOG reactivity in the CSF and serum of people with HAND is heightened compared with those with noninflammatory neurological conditions. The people with HAND who are MOG immunopositive performed significantly worse on the HIV dementia scale and showed higher viral load in CSF. In a longitudinal study of HAND, a sustained antibody response was noted despite successful clearance of viral RNA.⁹¹ These data suggest that anti-MOG antibodies may serve as a valuable biomarker for detecting HAND. Of clinical significance, elevated CSF anti-MOG antibodies may assist clinicians in the challenging diagnosis of HAND. Given the limitations of the current data and the retrospective nature of the research, further validation is necessary to confirm these findings through extensive prospective studies or animal model experiments.

BDNF

BDNF, a crucial retrograde factor for the CNS neurons, plays a vital role in the differentiation, growth, and survival of neuronal cell populations.⁹² BDNF is prominently present in various brain regions linked to mood disorders, such as the hippocampus, prefrontal cortex, and amygdala, influencing neuroplasticity and memory functions.⁹³ BDNF is initially synthesized as pro-BDNF, which is then cleaved into pre-BDNF and further processed into mature BDNF via plasmin or metalloproteinases.⁹⁴ Acting through its receptors, p75 neurotrophin receptor and tyrosine kinase receptor B, BDNF impacts neurons diversely. Specifically, pro-BDNF can stimulate axonal degeneration via the p75 neurotrophin receptor, whereas mature BDNF primarily interacts with the Trk receptor.^94,95 The pro-BDNF isoform is associated with neurotoxicity, and the mature BDNF form is associated with neuroprotection.^94,95 The conversion of pro-BDNF into BDNF has been shown to be reduced in people living with HIV.⁹⁴ This reduction in BDNF levels causes synaptic injury and compromises neuronal function.^94,96,97 In the late stage of people living with HIV, various levels of synaptic pruning and neuronal apoptosis are observable in the brain.⁹⁸ Studies have demonstrated that pro-BDNF levels in people with HAND were significantly higher compared with people without HIV and those with HIV but without dementia.⁹⁴

Increased BDNF levels have been shown to decrease the odds of developing HAND.⁹⁹ Abassi et al.¹⁰⁰ characterized the relationship between HAND and CSF biomarker expression in ART-naïve people living with HIV in Rakai, Uganda. Importantly, they demonstrated that higher BDNF levels were associated with reduced chances of MND or HAD, as opposed to normal function or ANI. In other words, people with HAD showed lower CSF BDNF levels.¹⁰⁰ In addition, Avdoshina et al.¹⁰¹ investigated the impact of HIV-1 on neurotrophin levels, revealing that the serum of people living with HIV had lower BDNF concentrations compared with people without HIV. Their findings supported the idea that reduced levels of BDNF might contribute to T-cell apoptosis and neurological complications associated with HIV acquisition. In a study of protein changes in CSF of people living with HIV, clinical evidence suggested a strong correlation between the severity of neurological symptoms in people living with HIV and declining human BDNF levels.¹⁰² Therefore, so far, the evidence has suggested that BDNF can serve as an important substance for combating neuronal damage and neuroprotection.^102,103 In the future, endogenous BDNF can be used to monitor changes in HAND, whereas exogenous BDNF may be a promising tool for treating HAND.

Comparison of Biomarkers for Other Neurodegenerative Diseases

AD is the most prevalent form of dementia, so its body fluid biomarkers were compared with those of HAND. In our review, we not only summarized the characteristic changes and pathological mechanisms of five HAND-related biomarkers in CSF and blood but also compared these findings with neurodegenerative diseases (Tables 1 and 2). Compared with the studies of body fluid biomarkers (especially Aβ42, p-tau, and t-tau) in the other neurocognitive disease (such as AD), the reduction of Aβ42 levels in CSF and the decrease of the Aβ42/Aβ40 ratio and the increase of p-tau and t-tau have been included in the international AD diagnostic standard.¹⁰⁴ Due to the introduction of cART treatments for HIV, more people living with HIV are reaching ages when AD-like symptoms appear. There exists an overlapping area between the elderly population of people with HIV and AD.¹⁰⁵ In Mäkitalo’s report,¹⁰⁶ they described a person living with HIV who experienced cognitive decline at the age of 63. Her history and clinical presentation are consistent with AD. The biomarker profile showed an AD pattern with markedly lowered CSF Aβ42 and elevations of t-tau and p-tau. However, sAPPα and sAPPβ exhibit different patterns in AD compared with HAND.¹⁰⁶ This conclusion requires further validation with substantial data.

Table 1.

Cerebrospinal Fluid Biomarker Differences Between HIV-Associated Neurocognitive Dysfunction and Neurodegenerative Diseases

Pathology mechanism	Changes in HAND	Changes in AD
Amyloid accumulation	APPα and APPβ ↓²²	APPα and APPβ n¹¹¹ Aβ42 ↓^81,112–113 Aβ42/Aβ40 ↓¹¹³
	Aβ ↓³³
	Aβ or Aβ42 n^22,114
	Aβ42 ↓^56,57,58
	Aβ42 n⁶⁰
Tau pathology	t-tau ↑^56,57,71,114	t-tau ↑ and p-tau ↑^81,113
	p-tau ↑^56,57
	p-tau n^22,71,114
	p-tau ↓⁷²
	p-tau/t-tau ↓⁷¹
Neuronal injury	NFL ↑^{18,20,21,23,82,84,85}	NFL ↑⁸¹
Myelin damage	MOG ↑⁹¹
Neurotrophic factor deficiency	BDNF↓¹⁰⁰

n, no increase; ↓, decrease; ↑, increase; AD, Alzheimer’s disease; BDNF, brain-derived neurotrophic factor; CSF, cerebrospinal fluid; HAND, human immunodeficiency virus-associated neurocognitive dysfunction; MOG, myelin oligodendrocyte glycoprotein; NFL, neurofilament light chain.

Table 2.

Blood Biomarker Differences Between HAND and Neurodegenerative Diseases

Pathology mechanism	Changes in HAND	Changes in AD
Amyloid accumulation	Aβ↑⁵⁴	Aβ42↓^107–108
	Aβ42↑⁶⁰	Aβ42/Aβ40 ↓^107–108
		Aβ42↑¹⁰⁹
Neuronal injury	NFL↑^54,82,83,88	NFL↑¹¹⁰
Tau pathology		t-tau ↑ and p-tau ↑¹¹⁰
Myelin damage	MOG↑⁹¹

↓, decrease; ↑, increase; AD, Alzheimer’s disease; HAND, human immunodeficiency virus-associated neurocognitive dysfunction; MOG, myelin oligodendrocyte glycoprotein; NFL, neurofilament light chain.

In our review, Aβ42, p-tau, t-tau, or NFL in CSF or blood could not distinguish HAND from AD. Currently, relying solely on body fluid biomarkers to differentiate HAND from other cognitive disorders is not sufficient, and it must be combined with serological results and medical history.

Conclusions

After conducting an in-depth review of the available literature, we found that previous research on HAND and biomarkers for neurological injury mainly concentrated on samples of CSF or blood, with no relevant studies focusing on other bodily fluids such as urine or saliva. By systematically analyzing five biomarkers for neurological injury, we determined that these biomarkers are not specific to HAND alone.

Despite advancements in understanding the epidemiology and neuropathogenesis of HAND, no single biomarker has been identified that can accurately and sensitively detect early-stage disease across all clinical contexts. Although neurological injury biomarkers show strong correlations in CSF, their associations in blood are less pronounced, possibly due to dilution or modification of these markers in blood samples. This may limit their effectiveness for early screening but could still be used as prognostic indicators to track the progression of HAND.

Limitations

Our examination of fluid biomarkers for neurological injury in HAND is restricted in range, as it does not cover all research related to the five assessed biomarkers. Certain articles, such as summaries, abstracts, reviews, letters, or inaccessible complete manuscripts, have been excluded.

Future Outlook

Currently, there is no single biomarker available for the specific identification of HAND. With advancements in technology and society, it may be feasible in the future to identify a set of diagnostic biomarkers that can accurately identify and predict HAND development.

At the moment, studies assessing noninvasive fluid substances as possible biomarkers show assurance in capturing pathological modifications in individuals. Numerous fresh noninvasive fluid biomarkers have surfaced as valuable diagnostic and pathological objectives for AD. In the approaching years, we anticipate discovering an increasing quantity of noninvasive fluid biomarkers, which will bring positive implications for the diagnosis and prevention of HAND. Nonetheless, implementing fluid biomarkers into clinical practice for HAND poses significant challenges.

Footnotes

Acknowledgments

The authors are delighted to acknowledge all the authors from the included studies.

Authors’ Contributions

M.Y., X.Z., and D.Z.: Conceptualization of article, preparation of the first draft, and writing and review; Y.Z., J.W., Y.Z., and C.G.: Literature collection; X.Z. and LW.: Read and approved the final article. All authors have read and agreed to the published version of the article.

Ethics Approval and Consent to Participate

Not applicable.

Data Availability Statement

Not applicable.

Author Disclosure Statement

All authors declare that they have no competing interests.

Funding Information

This review was supported by the Foundation of Gansu Provincial Hospital (21GSSYC-49), Natural Science Foundation of Gansu Province (17JR5RA040), and Gansu Provincial Clinical Research Center for Laboratory Medicine (21JR7RA676).

References

Vastag

, Fira-Mladinescu

, Rosca

. HIV-Associated Neurocognitive Disorder (HAND): Obstacles to early neuropsychological diagnosis. Int J Gen Med, 2022; 15:4079–4090; doi: 10.2147/IJGM.S295859

Kamat

, Misra

, Cassol

, et al. A plasma biomarker signature of immune activation in HIV patients on antiretroviral therapy. PLoS One, 2012; 7(2):e30881; doi: 10.1371/journal.pone.0030881

Ances

, Ellis

. Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol, 2007; 27(1):86–92; doi: 10.1055/s-2006-956759

Antinori

, Arendt

, Becker

, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology, 2007; 69(18):1789–1799; doi: 10.1212/01.WNL.0000287431.88658.8b

Antinori

, Arendt

, Grant

, et al.; The Mind Exchange Working Group. Assessment, diagnosis, and treatment of HIV-Associated neurocognitive disorder: A consensus report of the mind exchange program. Clin Infect Dis, 2013; 56(7):1004–1017; doi: 10.1093/cid/cis975

Nightingale

, Dreyer

, Saylor

, et al. Moving on from HAND: Why we need new criteria for cognitive impairment in people with HIV and a proposed way forward. Clin Infect Dis, 2021; 73(6):1113–1118; doi: 10.1093/cid/ciab366

Livelli

, Vaida

, Ellis

, et al.; CHARTER Group. Correlates of HIV RNA concentrations in cerebrospinal fluid during antiretroviral therapy: A longitudinal cohort study. Lancet HIV, 2019; 6(7):e456–e462; doi: 10.1016/S2352-3018(19)30143-2

Heaton

, Clifford

, Franklin Jr

, et al.; CHARTER Group. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology, 2010; 75(23):2087–2096; doi: 10.1212/WNL.0b013e318200d727

Wei

, Hou

, Su

, et al. The prevalence of Frascati-criteria-based HIV-associated neurocognitive disorder (HAND) in HIV-infected adults: A systematic review and meta-analysis. Front Neurol, 2020; 11:581346; doi: 10.3389/fneur.2020.581346

10.

Haddow

, Floyd

, Copas

, et al. A systematic review of the screening accuracy of the HIV Dementia Scale and International HIV Dementia Scale. PLoS One, 2013; 8(4):e61826; doi: 10.1371/journal.pone.0061826

11.

, Murray

, Steyerberg

, et al. Effects of Glasgow Outcome Scale misclassification on traumatic brain injury clinical trials. J Neurotrauma, 2008; 25(6):641–651; doi: 10.1089/neu.2007.0510

12.

Robertson

, Smurzynski

, Parsons

, et al. The prevalence and incidence of neurocognitive impairment in the HAART era. Aids, 2007; 21(14):1915–1921; doi: 10.1097/QAD.0b013e32828e4e27

13.

Sacktor

, McDermott

, Marder

, et al. HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol, 2002; 8(2):136–142; doi: 10.1080/13550280290049615

14.

Smail

, Brew

. HIV-associated neurocognitive disorder. Handb Clin Neurol, 2018; 152:75–97; doi: 10.1016/B978-0-444-63849-6.00007-4

15.

Rao

, Ruiz

, Prasad

. Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND). AIDS Res Ther, 2014; 11:13; doi: 10.1186/1742-6405-11-13

16.

Gartner

, Liu

. Insights into the role of immune activation in HIV neuropathogenesis. J Neurovirol, 2002; 8(2):69–75; doi: 10.1080/1355028029 0049525

17.

Naveed

, Fox

, Wichman

, et al. An assessment of factors associated with neurocognitive decline in people living with HIV. Int J STD AIDS, 2022; 33(1):38–47; doi: 10.1177/09564624211043351

18.

Mellgren

, Price

, Hagberg

, et al. Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection. Neurology, 2007; 69(15):1536–1541; doi: 10.1212/01.wnl.0000277635.05973.55

19.

Gisslén

, Krut

, Andreasson

, et al. Amyloid and tau cerebrospinal fluid biomarkers in HIV infection. BMC Neurol, 2009; 9:63; doi: 10.1186/1471-2377-9-63

20.

Gisslén

, Hagberg

, Brew

, et al. Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex. J Infect Dis, 2007; 195(12):1774–1778; doi: 10.1086/518043

21.

Jessen Krut

, Mellberg

, Price

, et al. Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients. PLoS One, 2014; 9(2):e88591; doi: 10.1371/journal.pone.0088591

22.

Peterson

, Gisslen

, Zetterberg

, et al. Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: Hierarchy of injury and detection. PLoS One, 2014; 9(12):e116081; doi: 10.1371/journal.pone.0116081

23.

Abdulle

, Mellgren

, Brew

, et al. CSF neurofilament protein (NFL)—A marker of active HIV-related neurodegeneration. J Neurol, 2007; 254(8):1026–1032; doi: 10.1007/s00415-006-0481-8

24.

Angel

, Jacobs

, Spudich

, et al. The cerebrospinal fluid proteome in HIV infection: Change associated with disease severity. Clin Proteomics, 2012; 9(1):3; doi: 10.1186/1559-0275-9-3

25.

Brien

RJO

, Wong

. Amyloid precursor protein processing and Alzheimer’s Disease. Annu Rev Neurosci, 2011; 34:185–204; doi: 10.1146/annurev-neuro-061010-113613

26.

De Strooper

, Annaert

. Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci, 2000; 113(Pt 11):1857–1870; doi: 10.1242/jcs.113.11.1857

27.

Andreasson

, Portelius

, Andersson

, et al. Aspects of beta-amyloid as a biomarker for Alzheimer’s disease. Biomark Med, 2007; 1(1):59–78; doi: 10.2217/17520363.1.1.59

28.

, Ikezu

. The comorbidity of HIV-associated neurocognitive disorders and Alzheimer’s disease: A foreseeable medical challenge in post-HAART era. J Neuroimmune Pharmacol, 2009; 4(2):200–212; doi: 10.1007/s11481-008-9136-0

29.

Brew

, Crowe

, Landay

, et al. Neurodegeneration and ageing in the HAART era. J Neuroimmune Pharmacol, 2009; 4(2):163–174; doi: 10.1007/s11481-008-9143-1

30.

Esiri

, Biddolph

, Morris

. Prevalence of Alzheimer plaques in AIDS. J Neurol Neurosurg Psychiatry, 1998; 65(1):29–33; doi: 10.1136/jnnp.65.1.29

31.

Howdle

, Quidé

, Kassem

, et al. Brain amyloid in virally suppressed HIV-associated neurocognitive disorder. Neurol Neuroimmunol Neuroinflamm, 2020; 7(4):e739; doi: 10.1212/NXI.0000000 000000739

32.

Alvarez

, Winston

, Barlow

, et al. Modulation of Amyloid-β and Tau in Alzheimer’s disease plasma neuronal-derived extracellular vesicles by Cerebrolysin® and Donepezil. J Alzheimers Dis, 2022; 90(2):705–717; doi: 10.3233/JAD-220575

33.

, McLaurin

, Mactutus

, et al. Intraneuronal β-Amyloid accumulation: Aging HIV-1 human and HIV-1 transgenic rat brain. Viruses, 2022; 14(6):1268; doi: 10.3390/v14061268

34.

Glenner

, Wong

. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun, 1984; 120(3):885–890; doi: 10.1016/s0006-291x(84)80190-4

35.

Lee

, Gillman

, Jang

, et al. Role of the fast kinetics of pyroglutamate-modified amyloid-β oligomers in membrane binding and membrane permeability. Biochemistry, 2014; 53(28):4704–4714; doi: 10.1021/bi500587p

36.

Tofoleanu

, Buchete

. Alzheimer Aβ peptide interactions with lipid membranes: Fibrils, oligomers and polymorphic amyloid channels. Prion, 2012; 6(4):339–345; doi: 10.4161/pri.21022

37.

Butterfield

, Sultana

. Methionine-35 of aβ (1–42): Importance for oxidative stress in Alzheimer disease. J Amino Acids, 2011; 2011:198430; doi: 10.4061/2011/198430

38.

Jana

, Pahan

. Fibrillar amyloid-beta-activated human astroglia kill primary human neurons via neutral sphingomyelinase: Implications for Alzheimer’s disease. J Neurosci, 2010; 30(38):12676–12689; doi: 10.1523/JNEUROSCI.1243-10.2010

39.

Varga

, Juhász

, Bozsó

, et al. Amyloid-β1–42 disrupts synaptic plasticity by altering glutamate recycling at the synapse. J Alzheimers Dis, 2015; 45(2):449–456; doi: 10.3233/JAD-142367

40.

Lim

, Iyer

, Ronco

, et al. Amyloid beta deregulates astroglia mGluR5-mediated calcium signaling via calcineurin and Nf-kB. Glia, 2013; 61(7):1134–1145; doi: 10.1002/glia.22502

41.

Aksenov

, Aksenova

, Mactutus

, Booze

. HIV-1 protein-mediated amyloidogenesis in rat hippocampal cell cultures. Neurosci Lett, 2010; 475(3):174–178; doi: 10.1016/j.neulet.2010.03.073

42.

Achim

, Adame

, Dumaop

, et al.; Neurobehavioral Research Center. Increased accumulation of intraneuronal amyloid beta in HIV-infected patients. J Neuroimmune Pharmacol, 2009; 4(2):190–199; doi: 10.1007/s11481-009-9152-8

43.

Jana

, Keskin

, Yaşar

. Molecular insight into the effect of HIV-TAT protein on Amyloid-β peptides. ACS Omega, 2024; 9(25):27480–27491; doi: 10.1021/acsomega.4c02643

44.

András

, Eum

, Huang

, Zhong

, Hennig

, Toborek

. HIV-1-induced amyloid beta accumulation in brain endothelial cells is attenuated by simvastatin. Mol Cell Neurosci, 2010; 43(2):232–243; doi: 10.1016/j.mcn.2009.11.004

45.

Daily

, Nath

, Hersh

. Tat petides inhibit neprilysin J. J Neurovirol, 2006; 12(3):153–160; doi: 10.1080/13550280600760677

46.

Chen

, Wu

, Yu

, et al. Rho-kinase inhibitor hydroxyfasudil protects against HIV-1 Tat-induced dysfunction of tight junction and neprilysin/Aβ transfer receptor expression in mouse brain microvessels. Mol Cell Biochem, 2021; 476(5):2159–2170; doi: 10.1007/s11010-021-04056-x

47.

Huang

, Guan

, Booze

, et al. Estrogen regulates neprilysin activity in rat brain. Neurosci Lett, 2004; 367(1):85–87; doi: 10.1016/j.neulet.2004.05.085

48.

Hategan

, Bianchet

, Steiner

, et al. HIV-Tat protein and amyloid β peptide form multifibrillar structures that cause neurotoxicity. Nat Struct Mol Biol, 2017; 24(4):379–386; doi: 10.1038/nsmb.3379

49.

Green

, Masliah

, Vinters

, et al. Brain deposition of β-amyloid is a common pathologic feature in HIV positive patients. Aids, 2005; 19(4):407–411; doi: 10.1097/01.aids.0000161770.06158.5c

50.

Takami

, Nagashima

, Sano

, et al. Gamma-secretase: Successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci, 2009; 29(41):13042–13052; doi: 10.1523/JNEUROSCI.2362-09.2009

51.

Olsson

, Schmidt

, Althoff

, et al. Characterization of intermediate steps in amyloid beta (Aβ) production under near-native conditions. J Biol Chem, 2014; 289(3):1540–1550; doi: 10.1074/jbc.M113.498246

52.

Jarrett

, Berger

, Lansbury

. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer’s disease. Biochemistry, 1993; 32(18):4693–4697; doi: 10.1021/bi00069a001

53.

Roher

, Lowenson

, Clarke

, et al. beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: Implications for the pathology of Alzheimer disease. Proc Natl Acad Sci U S A, 1993; 90(22):10836–10840; doi: 10.1073/pnas.90.22.10836

54.

Sun

, Dalvi

, Abadjian

, et al. Blood neuron—derived exosomes as biomarkers of cognitive impairment in HIV. Aids, 2017; 31(14):F9–F17; doi: 10.1097/QAD.0000000000001595

55.

Andras

, Leda

, Contreras

, et al. Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology. Mol Cell Neurosci, 2017; 79:12–22; doi: 10.1016/j.mcn.2016.12.006

56.

Brew

, Pemberton

, Blennow

, et al. CSF amyloid β42 and tau levels correlate with AIDS dementia complex. Neurology, 2005; 65(9):1490–1492; doi: 10.1212/01.wnl.0000183293.95787.b7

57.

Clifford

, Fagan

, Holtzman

, et al. CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease. Neurology, 2009; 73(23):1982–1987; doi: 10.1212/WNL.0b013e3181c5b445

58.

Guha

, Misra

, Chettimada

, et al. CSF extracellular vesicle Aβ42 and Tau/Aβ42 ratio are associated with cognitive impairment in older people with HIV. Viruses, 2023; 16(1):72; doi: 10.3390/v16010072

59.

Calcagno

, Atzori

, Romito

, et al. Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive patients. J Neurovirol, 2016; 22(1):88–92; doi: 10.1007/s13365-015-0371-x

60.

Mothapo

, Stelma

, Janssen

, et al. Amyloid beta-42 (Aβ-42), neprilysin and cytokine levels, A pilot study in patients with HIV related cognitive impairments. J Neuroimmunol, 2015; 282:73–79; doi: 10.1016/j.jneuroim.2015.03.017

61.

Kiris

, Ventimiglia

, Feinstein

. Quantitative analysis of MAP-mediated regulation of microtubule dynamic instability in vitro. Methods Cell Biol, 2010; 95:481–503; doi: 10.1016/S0091-679X(10)95024-3

62.

Braak

, Braak

. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging, 1997; 18(4):351–357; doi: 10.1016/s0197-4580(97)00056-0

63.

Petzold

. Neurofilament phosphoforms: Surrogate markers for axonal injury, degeneration and loss. J Neurol Sci, 2005; 233(1–2):183–198; doi: 10.1016/j.jns.2005.03.015

64.

Delacourte

, Sergeant

, Wattez

, et al. Tau aggregation in the hippocampal formation: An ageing or a pathological process? Exp Gerontol, 2002; 37(10–11):1291–1296; doi: 10.1016/s0531-5565(02)00141-9

65.

Lee

, Rizer

, Selenica

, et al. LPS-induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. J Neuroinflammation, 2010; 7:56; doi: 10.1186/1742-2094-7-56

66.

Blennow

, Hampel

, Weiner

, et al. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol, 2010; 6(3):131–144; doi: 10.1038/nrneurol.2010.4

67.

Murray

, Kouri

, Lin

, et al. Clinicopathologic assessment and imaging of tauopathies in neurodegenerative dementias. Alzheimers Res Ther, 2014; 6(1):1; doi: 10.1186/alzrt231

68.

Anthony

, Ramage

, Carnie

, et al. Accelerated Tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active anti-retoviral therapy. Acta Neuropathol, 2006; 111(6):529–538; doi: 10.1007/s00401-006-0037-0

69.

Gonzalez

, Wilson

, Byrd

, et al. Neuronal accumulation of hyperphosphorylated tau protein predicts stable memory impairment in people living with HIV. Aids, 2023; 37(8):1247–1256; doi: 10.1097/QAD0000000000003556

70.

Patrick

, Crews

, Desplats

, et al. Increased CDK5 expression in HIV encephalitis contributes to neurodegeneration via tau phosphorylation and is reversed with Roscovitine. Am J Pathol, 2011; 178(4):1646–1661; doi: 10.1016/j.ajpath.2010.12.033

71.

Krut

, Price

, Zetterberg

, et al. No support for premature central nervous system aging in HIV-1 when measured by cerebrospinal fluid phosphorylated tau (p-tau). Virulence, 2017; 8(5):599–604; doi: 10.1080/21505594.2016.1212155

72.

Ozturk

, Kollhoff

, Anderson

, et al. Linked CSF reduction of phosphorylated tau and IL-8 in HIV associated neurocognitive disorder. Sci Rep, 2019; 9(1):8733; doi: 10.1038/s41598-019-45418-2

73.

Rowe

, Ng

, Ackermann

, et al. Imaging β-amyloid burden in aging and dementia. Neurology, 2007; 68(20):1718–1725; doi: 10.1212/01.wnl.0000261919.22630.ea

74.

Fagan

, Head

, Shah

, et al. Decreased cerebrospinal fluid Abeta (42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol, 2009; 65(2):176–183; doi: 10.1002/ana.21559

75.

Jung

, Son

, Kwon

, et al. Non-Invasive nasal discharge fluid and other body fluid biomarkers in alzheimer’s disease. Pharmaceutics, 2022; 14(8):1532; doi: 10.3390/pharmaceutics14081532

76.

Niikado

, Chrem-Méndez

, Itzcovich

, et al. Evaluation of cerebrospinal fluid neurofilament light chain as a routine biomarker in a memory clinic. J Gerontol A Biol Sci Med Sci, 2019; 74(4):442–445; doi: 10.1093/gerona/gly179

77.

Yuan

, Nixon

. Neurofilament proteins as biomarkers to monitor neurological25 diseases and the efficacy of therapies. Front Neurosci, 2021; 15:689938; doi: 10.3389/fnins.2021.689938

78.

Malka-Gibor

, Kornreich

, Laser-Azogui

, et al. Phosphorylation-Induced mechanical regulation of intrinsically disordered neurofilament proteins. Biophys J, 2017; 112(5):892–900; doi: 10.1016/j.bpj.2016.12.050

79.

Yuan

, Rao

, Nixon

, et al. Neurofilaments and neurofilament proteins in health and disease. Cold Spring Harb Perspect Biol, 2017; 9(4):a018309; doi: 10.1101/cshperspect.a018309

80.

Idland

, Sala-Llonch

, Borza

, et al. CSF neurofilament light levels predict hippocampal atrophy in cognitively healthy older adults. Neurobiol Aging, 2017; 49:138–144; doi: 10.1016/j.neurobiolaging

81.

Dhiman

, Gupta

, Villemagne

, et al. Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer’s disease. Lzheimers Dement (Amst), 2020; 12(1):e12005; doi: 10.1002/dad2.12005

82.

Gisslén

, Price

, Andreasson

, et al. Plasma concentration of the Neurofilament Light Protein (NFL) is a biomarker of CNS injury in HIV infection: A cross-sectional study. EBioMedicine, 2016; 3:135–140; doi: 10.1016/j.ebiom.2015.11.036

83.

Anderson

, Easley

, Kasher

, et al. Neurofilament light chain in blood is negatively associated with neuropsychological performance in HIV-infected adults and declines with initiation of antiretroviral therapy. J Neurovirol, 2018; 24(6):695–701; doi: 10.1007/s13365-018-0664-y

84.

Eden

, Marcotte

, Heaton

, et al. Increased intrathecal immune activation in virally suppressed HIV-1 infected patients with neurocognitive impairment. PLoS One, 2016; 11(6):e0157160; doi: 10.1371/journal.pone.0157160

85.

Yilmaz

, Blennow

, Hagberg

, et al. Neurofilament light chain protein as a marker of neuronal injury: Review of its use in HIV-1 infection and reference values for HIV-negative controls. Expert Rev Mol Diagn, 2017; 17(8):761–770; doi: 10.1080/14737159.2017.1341313

86.

McGuire

, Gill

, Douglas

, et al; CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group. Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. J Neurovirol, 2015; 21(4):439–448; doi: 10.1007/s13365-015-0333-3

87.

Calcagno

, Cusato

, Cinque

, et al. Serum and CSF biomarkers in asymptomatic patients during primary HIV infection: A randomized study. Brain, 2024; 147(11):3742–3750; doi: 10.1093/brain/awae271

88.

Rocha

, Teixeira

, Colpo

, et al. Blood biomarkers of neuronal/axonal and glial injury in human immunodeficiency virus-associated neurocognitive disorders. Dement Geriatr Cogn Disord, 2022; 51(6):467–474; doi: 10.1159/000527659

89.

Peschl

, Bradl

, Höftberger

, et al. Myelin oligodendrocyte glycoprotein: Deciphering a target in inflammatory demyelinating diseases. Front Immunol, 2017; 8:529; doi: 10.3389/fimmu.2017.00529

90.

Gadama

, Preez

, Carr

, et al. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and Human Immunodeficiency virus infection: Dilemmas in diagnosis and management: A case series. J Med Case Rep, 2023; 17(1):457; doi: 10.1186/s13256-023-04191-7

91.

Lackner

, Kuenz

, Reindl

, et al. Antibodies to myelin oligodendrocyte glycoprotein in HIV-1 associated neurocognitive disorder: A cross-sectional cohort study. J Neuroinflammation, 2010; 7:79; doi: 10.1186/1742-2094-7-79

92.

Segal

, Greenberg

. Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci, 1996; 19:463–489; doi: 10.1146/annurev.ne.19.030196.002335

93.

Schmitt

, Holsboer-Trachsler

, Eckert

. BDNF in sleep, insomnia, and sleep deprivation. Ann Med, 2016; 48(1–2):42–51; doi: 10.3109/07853890.2015.1131327

94.

Bachis

, Avdoshina

, Zecca

, et al. Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons. J Neurosci, 2012; 32(28):9477–9484; doi: 10.1523/JNEUROSCI0865 -12.2012

95.

Eyileten

, Kaplon-Cieslicka

, Mirowska-Guzel

, et al. Antidiabetic effect of brain-derived neurotrophic factor and its association with inflammation in type 2 diabetes mellitus. J Diabetes Res, 2017; 2017:2823671; doi: 10.1155/2017/2823671

96.

Greenberg

, Xu

, Lu

, et al. New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci, 2009; 29(41):12764–12767; doi: 10.1523/JNEUROSCI.3566-09.2009

97.

Speidell

, Asuni

, Avdoshina

, et al. Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin Receptor. Front Cell Neurosci, 2019; 13:398; doi: 10.3389/fncel.2019.00398

98.

Ellis

, Langford

, Masliah

. HIV and antiretroviral therapy in the brain: Neuronal injury and repair. Nat Rev Neurosci, 2007; 8(1):33–44; doi: 10.1038/nrn2040

99.

Nosheny

, Mocchetti

, Bachis

. Brain-derived neurotrophic factor as a prototype neuroprotective factor against HIV-1-associated neuronal degeneration. Neurotox Res, 2005; 8(1–2):187–198; doi: 10.1007/BF03033829

100.

Abassi

, Morawski

, Nakigozi

, et al. Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda. J Neurovirol, 2017; 23(3):369–375; doi: 10.1007/s13365-016-0505-9

101.

Avdoshina

, Garzino-Demo

, Bachis

, et al. HIV-1 decreases the levels of neurotrophins in human lymphocytes. Aids, 2011; 25(8):1126–1128; doi: 10.1097/QAD.0b013e32834671b3

102.

Meeker

, Poulton

, Markovic-Plese

, et al. Protein changes in CSF of HIV-infected patients: Evidence for loss of neuroprotection. J Neurovirol, 2011; 17(3):258–273; doi: 10.1007/s13365-011-0034-5

103.

Tong

, Buch

, Yao

, et al. Monocytes-Derived macrophages mediated stable expression of human brain-derived neurotrophic factor, a novel therapeutic strategy for NeuroAIDS. PLoS One, 2014; 9(2):e82030; doi: 10.1371/journal.pone.0082030

104.

Jack

Jr , Bennett

, Blennow

, et al.; Contributors. NIA-AA research framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement, 2018; 14(4):535–562; doi: 10.1016/j.jalz.2018.02.018

105.

Farhadian

, Patel

, Spudich

. Neurological complications of HIV infection. Curr Infect Dis Rep, 2017; 19(12):50; doi: 10.1007/s11908-017-0606-5

106.

Mäkitalo

, Mellgren

, Borgh

, et al. The cerebrospinal fluid biomarker profile in an HIV-infected subject with Alzheimer’s disease. AIDS Res Ther, 2015; 12:23; doi: 10.1186/s12981-015-0063-x

107.

Lee

, Kim

, Hong

, et al. Diagnosis of Alzheimer’s disease utilizing amyloid and tau as fluid biomarkers. Exp Mol Med, 2019; 51(5):1–10; doi: 10.1038/s12276-019-0250-2

108.

Janelidze

, Stomrud

, Palmqvist

, et al. Plasma β-amyloid in Alzheimer’s disease and vascular disease. Sci Rep, 2016; 6:26801; doi: 10.1038/srep26801

109.

Chen

, Lai

, Ke

, et al. Changes in plasma amyloid and tau in a longitudinal study of normal aging, mild cognitive impairment, and alzheimer’s disease. Dement Geriatr Cogn Disord, 2019; 48(3–4):180–195; doi: 10.1159/000505435

110.

Garcia-Escobar

, Manero

, Fernández-Lebrero

, et al. Blood biomarkers of alzheimer’s disease and cognition: A literature review. Biomolecules, 2024; 14(1):93; doi: 10.3390/biom14010093

111.

Olsson

, Höglund

, Sjögren

, et al. Measurement of alpha-and beta-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients. Exp Neurol, 2003; 183(1):74–80; doi: 10.1016/s0014-4886(03)00027-x

112.

Boumenir

, Cognat

, Sabia

, et al. CSF level of β-amyloid peptide predicts mortality in Alzheimer’s disease. Alzheimers Res Ther, 2019; 11(1):29; doi: 10.1186/s13195-019-0481-4

113.

Tariciotti

, Casadei

, Honig

, et al. Clinical experience with cerebrospinal fluid Aβ42, total and phosphorylated tau in the evaluation of 1,016 individuals for suspected dementia. J Alzheimers Dis, 2018; 65(4):1417–1425; doi: 10.3233/JAD-180548

114.

Steinbrink

, Evers

, Buerke

, et al.; German Competence Network HIV/AIDS. Cognitive impairment in HIV infection is associated with MRI and CSF pattern of neurodegeneration. Eur J Neurol, 2013; 20(3):420–428; doi: 10.1111/ene.12006