HIV-associated neurocognitive disorders (HAND) are neurological disorders associated with
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...
and
AIDS. It is a syndrome of progressive deterioration of memory, cognition, behavior, and motor function in HIV-infected individuals during the late stages of the disease, when immunodeficiency is severe. HAND may include neurological disorders of various severity. HIV-associated neurocognitive disorders are associated with a metabolic
encephalopathy
Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...
induced by HIV infection and fueled by immune activation of
macrophages and
microglia.
[
] These cells are actively infected with HIV and secrete
neurotoxins of both host and viral origin. The essential features of HIV-associated dementia (HAD) are disabling cognitive impairment accompanied by motor dysfunction, speech problems and behavioral change.
Cognitive impairment is characterised by mental slowness, trouble with
memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered ...
and poor
concentration
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', '' number concentration'', ...
. Motor symptoms include a loss of fine motor control leading to clumsiness, poor balance and tremors. Behavioral changes may include
apathy
Apathy is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic individual has an absence of intere ...
,
lethargy
Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overwo ...
and diminished emotional responses and spontaneity.
Histopathologically
Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία ''-logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Spec ...
, it is identified by the infiltration of
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s and
macrophages into the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS),
gliosis
Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, ...
, pallor of
myelin sheath
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
s, abnormalities of
dendritic
Dendrite derives from the Greek word "dendron" meaning ( "tree-like"), and may refer to:
Biology
*Dendrite, a branched projection of a neuron
*Dendrite (non-neuronal), branching projections of certain skin cells and immune cells
Physical
* Dendr ...
processes and
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
al loss.
[
]
HAD typically occurs after years of HIV infection and is associated with low CD4+ T cell levels and high plasma viral loads. It is sometimes seen as the first sign of the onset of AIDS. Prevalence is between 10 and 24% in Western countries[
] and has only been seen in 1–2% of India-based infections.[
][
] With the advent of highly active antiretroviral therapy
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multip ...
(HAART), the incidence of HAD has declined in developed countries
A developed country (or industrialized country, high-income country, more economically developed country (MEDC), advanced country) is a sovereign state that has a high quality of life, developed economy and advanced technological infrastruct ...
, although its prevalence
In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
is increasing. HAART may prevent or delay the onset of HAD in people with HIV infection, and may also improve mental function in people who already have HAD.
Dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
only exists when neurocognitive impairment in the patient is severe enough to interfere markedly with day-to-day function. That is, the patient is typically unable to work and may not be able to take care of themself. Before this, the patient is said to have a mild neurocognitive disorder.
Presentation
Cognitive impairments associated with HIV occur in the domains of attention, memory, verbal fluency, and visuospatial construction. Specifically for memory, the lowered activity of the hippocampus changes the basis for memory encoding and affects mechanisms such as long-term potentiation. Severity of impairment in different domains varies depending on whether or not a patient is being treated with HAART or monotherapy. Studies have shown that patients exhibit cognitive deficits consistent with dysfunction of fronto-striatal circuits including associated parietal areas, the latter of which may account for observed deficits in visuospatial function. In addition to cognitive impairments, psychological dysfunction is also noted. For example, patients with HIV have higher rates of clinical depression
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...
and alexithymia, i.e., difficulty processing or recognizing one's own emotions.[ Patients also have more difficulty recognizing facial emotions.]
Without combination antiretroviral therapy, cognitive impairments increase with successive stages of HIV. HIV patients in early stages show mild difficulties in concentration and attention. In advanced cases of HIV-associated dementia, speech delay, motor dysfunction, and impaired thought and behavior are observed.[ Specifically, lower motor speeds were found to correlate with hypertrophy of the right putamen.][
The diagnosis of HIV-associated neurocognitive impairment is made using clinical criteria after considering and ruling out other possible causes.][ The severity of neurocognitive impairment is associated with nadir CD4, suggesting that earlier treatment to prevent immunosuppression due to HIV may help prevent HIV-associated neurocognitive disorders.][
]
Pathophysiology
HIV-associated dementia (HAD) is not a true opportunistic infection; it is one of the few conditions caused directly by HIV itself. However, the cause of HAD can be difficult to discern because the central nervous system can be damaged by a number of other causes related to HIV infection:
* opportunistic infections
* AIDS-related lymphoma
AIDS-related lymphoma describes lymphomas occurring in patients with acquired immunodeficiency syndrome ( AIDS).
A lymphoma is a type of cancer arising from lymphoid cells. In AIDS, the incidences of non-Hodgkin's lymphoma, primary cerebral lymp ...
or metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...
of other AIDS-related cancers
* direct effects of HIV in the brain
* toxic effects of drug treatments
* malnutrition
Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues ...
Many researchers believe that HIV damages the vital brain cells, neurons, indirectly. According to one theory, HIV either infects or activates cells that protect the brain, known as macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
and microglia. These cells then produce toxins that can set off a series of reactions that instruct neurons to self-destruct. The infected macrophages and microglia also appear to produce additional factors such as chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...
s and cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s that can affect neurons as well as other brain cells known as astrocyte
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...
s. The affected astrocytes, which normally nurture and protect neurons, also may now end up harming neurons. Astrocytes produce neurotoxic proteins such as Tat, Nef and Rev. Tat is secreted and induces reactivity in astrocytes through increased GFAP expression. HIV protein gp120
Envelope glycoprotein GP120 (or gp120) is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1988. The 120 in its name comes from ...
inhibits the stem cells in the brain from producing new nerve cells. In the neuronal cells, the HIV gp120 induces mitochondrial-death proteins like caspases, which may influence the upregulation of the death receptor Fas leading to apoptosis.
Direct effects of HIV
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
enters the brain early on in the infection. It is thought that HIV uses a "Trojan horse
The Trojan Horse was a wooden horse said to have been used by the Greeks during the Trojan War to enter the city of Troy and win the war. The Trojan Horse is not mentioned in Homer's ''Iliad'', with the poem ending before the war is concluded, ...
" mechanism to enter the brain. Normally, the blood–brain barrier (BBB) serves as a protective mechanism by preventing entry of foreign substances; disruption of the BBB by HIV contributes to the progression of infection. The virus is able to enter the brain through infected cells that pass through the BBB to replace the immune cells surrounding the blood supply in the brain. When infected, immune cells are able to better migrate into tissues compared to uninfected cells. Infected microglia add to the production of the virus. This activation of the microglia may contribute to the process of neuropathogenesis that spreads the infection to nearby cells. Other cells that can get infected include the astrocytes, which can trigger bystander cellular dysfunction and apoptosis, further compromising the blood–brain barrier. The toxicity spreads through a gap junction-dependent mechanism.
Brain regions affected
HIV is associated with pathological changes in mainly subcortical and fronto-striatal areas of the brain, including the basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
, deep white matter, and hippocampal
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...
regions. Neuroimaging studies of HIV patients indicate that significant volume reductions are apparent in the frontal white matter, whereas subcortically, hypertrophy is apparent in the basal ganglia, especially the putamen
The putamen (; from Latin, meaning "nutshell") is a round structure located at the base of the forebrain (telencephalon). The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that compose the basal ...
. Moreover, the results of some studies suggest loss of brain volume in cortical and subcortical regions even in asymptomatic HIV patients and patients who were on stable treatment.[ A recent longitudinal study of a small representative cohort of HIV-positive patients on stable medication regiments suggests that this cortical atrophy is progressive, and is in part related to nadir CD4. Cerebral brain volume is associated with factors related to duration of the disease and CD4 nadir; patients with a longer history of chronic HIV and higher CD4 nadir loss present with greater cerebral atrophy.] CD4 lymphocyte counts have also been related to greater rates of brain tissue loss. Current factors, such as plasma HIV RNA, have been found to be associated with brain volumes as well, especially with regards to basal ganglia volume[ and total white matter. Loss of cortical grey matter oligodendrocytes might also contribute to the symptomatology.]
Changes in the brain may be ongoing but asymptomatic, that is with minimal interference in functioning, making it difficult to diagnose HIV-associated neurocognitive disorders in the early stages.
Diagnostic criteria
# Marked acquired impairment of at least two ability domains of cognitive function (e.g. memory, attention): typically, the impairment is in multiple domains, especially in learning, information processing and concentration/attention. The cognitive impairment is ascertained by medical history
The medical history, case history, or anamnesis (from Greek: ἀνά, ''aná'', "open", and μνήσις, ''mnesis'', "memory") of a patient is information gained by a physician by asking specific questions, either to the patient or to other peo ...
, mental status examination or neuropsychological testing.
# Cognitive impairments identified in 1 interfere markedly with day-to-day functioning.
# Cognitive impairments identified in 1 are present for at least one month.
# Cognitive impairments identified in 1 do not meet the criteria for delirium, or if delirium is present, dementia was diagnosed when delirium was not present.
# No evidence of another, pre-existing cause that could explain the dementia (e.g. another CNS infection, CNS neoplasm, cerebrovascular disease, pre-existing neurological disease, severe substance abuse compatible with CNS disorder.[
]
While the progression of dysfunction is variable, it is regarded as a serious complication and untreated can progress to a fatal outcome. Diagnosis is made by neurologist
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
s who carefully rule out alternative diagnoses. This routinely requires a careful neurological examination, brain scans (MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
or CT scan) and a lumbar puncture to evaluate the cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...
. No single test is available to confirm the diagnosis, but the constellation of history, laboratory findings and examination can reliably establish the diagnosis when performed by experienced clinicians. The amount of virus in the brain does not correlate well with the degree of dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
, suggesting that secondary mechanisms are also important in the manifestation of HAD.
HAD stage characteristics
* Stage 0 ''(Normal)'' Normal Mental and Motor Function
Motor control is the regulation of movement in organisms that possess a nervous system. Motor control includes reflexes as well as directed movement.
To control movement, the nervous system must integrate multimodal sensory information (both ...
* Stage 0.5 ''(Subclinical)'' Minimal symptoms of cognitive or motor dysfunction characteristic of HAD, or mild signs ( snout response, slowed extremity movements), but without impairment of work or capacity to perform activities of daily living (ADL). Gait and strength are normal.
* Stage 1 ''(Mild)'' Evidence of functional intellectual or motor impairment characteristic of HAD, but able to perform all but the more demanding aspects of work or ADL. Can walk without assistance.
* Stage 2 ''(Moderate)'' Cannot work or maintain the more demanding aspects of daily life, but able to perform basic activities of self care. Ambulatory, but may require a single prop.
* Stage 3 ''(Severe)'' Major intellectual incapacity - cannot follow news or personal events, cannot sustain complex conversation, considerable slowing of all output. And/or motor disability - cannot walk unassisted, requiring walker or personal support, usually with slowing and clumsiness of arms as well.
* Stage 4 ''(End Stage)'' Nearly vegetative. Intellectual and social comprehension and responses are at a rudimentary level. Nearly or absolutely mute. Paraparetic or paraplegic with urinary incontinence
Urinary incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a large impact on quality of life. It has been identified as an important issue in geri ...
and fecal incontinence
Fecal incontinence (FI), or in some forms encopresis, is a lack of control over defecation, leading to involuntary loss of bowel contents, both liquid stool elements and mucus, or solid feces. When this loss includes flatus (gas), it is referre ...
.
Neuroimaging studies
A study by Melrose et al. (2008) examined the integrity of the fronto-striatal circuitry that underlies executive functioning in HIV. Participants in the study were diagnosed with HIV three months to sixteen years before the study. Ten out of eleven patients were on antiretroviral medication and none scored within the demented range on the HIV Dementia Scale. It was found that HIV+ patients showed less activity within the ventral prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46 ...
(PFC) and left dorsolateral PFC. There was reduced connectivity between the left caudate and ventral PFC and between the left caudate and dorsolateral PFC compared to healthy controls. Additionally, there was hypoactivation of the left caudate in the HIV+ patients. In the control group, there was correlation between caudate activity and executive functioning as shown by performance on neuropsychological testing. Further analysis of the pathways in the HIV+ group involving left caudate showed reduced functional connectivity between the left caudate and globus pallidus (basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
output nucleus). This dysfunction with the basal ganglia and PFC may explain the executive function and semantic event sequencing task impairments noted in HIV+ patients included in this study.
The study by Melrose et al. (2008) also investigated parietal activation. It was found that anterior parietal activation in HIV+ patients was slightly anterior to that in control participants, which follows the idea that HIV causes a reorganization of the attention network leading to cognitive impairments. Additionally, the anterior parietal activity showed a relationship with caudate functioning, which implicates a compensatory mechanism set forth when damage to the fronto-striatal system occurs.[
Overall, the study by Melrose et al. (2008) showed that HIV in the brain is associated with cognitive impairments. Damage to the fronto-striatal system may underlie cognitive problems including executive function and sequencing tasks.
Another area of impairment due to fronto-striatal dysfunction is in the area of emotion recognition. In a study of HIV+ patients and control adults by Clark et al. (2010), it was shown that HIV patients demonstrate impairments in the recognition of fearful facial expressions. The authors suggested that fronto-striatal abnormalities related to HIV may underlie these impairments.][
In identification tasks, administered by Clark et al. (2010), HIV+ patients and control participants were asked to identify different facial emotions and landscapes, with these picture categories matched for image complexity. HIV+ patients did worse than the control group on the facial recognition task but not on landscape identification. In the facial emotion task, fear recognition was significantly worse in the HIV than in the control group.][
]
Neurodevelopmental disorders associated with infection
Mother-to-child transmission
A vertically transmitted infection is an infection caused by pathogenic bacteria or viruses that use mother-to-child transmission, that is, transmission directly from the mother to an embryo, fetus, or baby during pregnancy or childbirth. It can ...
during pregnancy is the dominant mode of acquisition of HIV infection in children and has been associated with an increased risk of mortality and developmental delay
Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech ...
. Children with AIDS appear to have neurological diseases as a consequence of HIV-1 infection. In HIV-1 infected newborn and children, central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS) is infected with HIV-1 weeks after primary infection, causing neuronal damage and cell death. Although neurological dysfunctions have been associated to HIV infection of the CNS, it is unclear how the pathogenesis of neurological disorders has been established.
The main cells infected by HIV-1 in the nervous tissue are the microglia, astrocytes and macrophages, whereas infected neurons have been rarely observed. The susceptibility to HIV-1 infection and replication in neuronal and glial cells is a function of cellular differentiation, and it is more likely in immature precursors than with differentiated cells.
Several soluble signals, such as cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s, have been described to modulate susceptibility and can further contribute in supporting virus latency or virus replication during organ development. In fact, within the developing CNS, cells are under the control of environmental factors that provide instructive signals to neural cell targets. By regulating the survival, differentiation and maintenance of specific functions of neuronal and glial precursors, these extracellular signals can influence many steps of the CNS development and concur in controlling virus-cell interactions in the maturing brain.
In addition to the production of cytokines, HIV-1 infected mononuclear cells and astrocytes can produce a number of soluble mediators, including viral proteins such as gp120
Envelope glycoprotein GP120 (or gp120) is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1988. The 120 in its name comes from ...
and Tat, that can exert damaging effects on both developing and mature neural tissues. Moreover, molecules such as the platelet activating factor (PAF) and prostaglandins, which are produced upon microglia/macrophages and astrocytes functional interactions, have been reported to mediate cell damage in primary neural cell cultures and neural cell lines with immature phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...
.
Taken together, these observations suggest that the mechanism by which the virus can alter CNS development and induce pathology in the immature brain may depend upon the altered production of soluble bioactive compounds. Several potentially neurotoxic mediators have been identified in different model systems, including inflammatory cytokines, viral proteins and neurotoxic metabolites. Thus, it is likely that a complex interaction of several mediators may alter the function and survival of actively developing and maturing cells, responsible for the neurologic disorders.
References
External links
{{Mental and behavioural disorders, selected = neurological
HIV/AIDS
Cognitive disorders
Dementia