**3. Gait/balance**

Aging is associated with a cascade of events affecting the function of the Substantia Nigra (SN) neurons, from the dopamine metabolism to the mitochondrial dysfunction and the alteration in protein degradation. The addition of cellular defects linked to aging increases the risks of developing Parkinson's disease [73, 74].

every motor task [96]. A psychomotor slowing of HIV patients was already described in early neuropsychological studies [97], which was presumed to be from the frontostriatal origin. The first hypothesis for the gait and balance problems was a neuropathy of the peripheral nervous system [98, 99]. However, the cerebellum, and the pons more exactly, is also implicated in

Brain Aging in HIV-1 Infection

9

http://dx.doi.org/10.5772/intechopen.77029

There is evidence of cerebellar damage [105–107] and an important degeneration of the cerebellar granular cell layer and axonal swelling. CT and MRI show pontocerebellar damage in HIV infection [108] and 3–6% of an HIV-infected group [109]. Men and women show tissue volume deficits in combined pons, vermis tissue, and cerebellar hemispheres. This will result in a deficit in motor performance like static postural stability, and tandem walking, particularly when the patients have their eyes closed during the test. The psychomotor speed and the

The pediatric HIV-1 infection will present different complications, involving deep abnormalities in the striatal dopamine system including the basal ganglia. The HIV-infected children present a slower-than-normal information processing and poor attentional abilities [110–112].

Epigenetic alterations are one of the hallmarks of aging. As epigenetic changes accumulate upon aging, DNA methylation can be a precise predictor of chronological age [113, 114], since

A first large-scale epigenome-wide association study in 2016 analyzed DNA methylation during HIV infection [116] and found a differential DNA methylation associated with the infection. HIV-1, as other viruses, can alter the expression of DNA methyltransferases (DNMTs), like DNMT1 [117, 118] and DNMT3b [119], affecting maintenance and de novo DNA methylation maintenance. The alteration of methylation could be an epigenetic outcome of the integration of HIV-1 DNA into the host genome and could decrease genome stability. These studies were made in blood, and because of the presence of the blood-brain barrier, it was

A 2015 study uses blood and brain tissue to find a relationship between HIV status and epigenetic age acceleration [120]. It eliminates different hypothesis explaining age acceleration effects in the brain tissue. It concluded that the telomere length is not involved and finds difficult to explain the age acceleration in the brain by the increase in the amount of senescent or exhausted T-cells like it is working in the blood, because of the blood-brain barrier. The retained hypothesis is an effect of the age acceleration, and independently the T-cells exhaust, confounding the relationship between these two events. In 2016, a comparative DNA methylation profiling on monocytes derived from HIV-infected individuals, with or without impairment, identifies a specific immunoepigenetic signature of cognitive impairment [121]. A total of 1032 loci differentially methylated are associated with cognitive impairment, with

HIV infection [100–105].

finger dexterity were also impaired.

certain CpG sites are highly associated with age [115].

necessary to analyze methylation directly in the brain tissue.

**4. Epigenetic changes**

**4.1. Methylation levels**

With aging, the density of dopamine transporters and dopaminergic neurons decreases, and there is a correlation between the decline of the dopamine system function and the executive function [75]. Several studies show evidence of a link between aging, memory, learning, and dopaminergic change [76–79]. HIV-1 penetrates the brain immediately after the initial infection and is disseminated in various concentrations in different parts of the brain, with a particular affinity for the subcortical regions like the basal ganglia, including the putamen, caudate nucleus, globus pallidus, and Substantia Nigra [80]. HIV-1 RNA is also identified in different regions of the postmortem brain, especially in different nuclei of the basal ganglia [81–83]. Since basal ganglia is the main target of HIV infection in the brain, it is not surprising that the dopaminergic function located in the Substantia Nigra will be altered. Neuropathological assessments of HIV+ patients show that the degeneration of Substantia Nigra is common. Moreover, it could explain the sensitivity of some patients to drug-induced Parkinsonism [84].

HIV-1 and Parkinson's disease both affect nigrostriatal structures with subsequent dopaminergic dysfunction. HIV-1 patients display signs of hypomimia, bradykinesia, poor hand agility, and action or postural tremor exacerbated by age [85]. The aging HIV+ population treated with HAART shows more frequent presentation of HIV-1 Parkinsonism. A significant decrease of dopamine in the Substantia Nigra was subsequently found in the postmortem examination of the HIV+ brains [86]. Alpha-synuclein is one of the major factors in Parkinson's disease pathology, and its expression was found to have increased in the Substantia Nigra of HIV+ postmortem brain [87]. Alpha-synuclein plays a role in the apoptosis of dopamine cells and reinforces the idea that the aging brain of HIV+ individuals may develop PD. Different studies report that the dopamine concentration in the HIV-infected brain can decrease by 50% [80, 86, 88]. The decrease in DA levels in SN was significantly correlated with the decrease in performance in learning, memory, speed of processing information, and verbal fluency.

The presynaptic dopamine transporter (DAT)-mediated dopamine reuptake is crucial for regular dopamine homeostasis and subsequent brain functions like memory, learning, and attention. However, it has been reported that HIV patients with dementia had substantially lower DAT availability in ventral striatum and putamen [89]. The DAT expression and function is also altered by HIV proteins in animals. HIV-1 Tat induces inhibition of the transporter by an allosteric binding to DAT [90]. DAT function and expression is modified in the HIV-1-tg rats [91]. HIV-1 gp120 was similarly described to cause a loss of dopamine-secreting neurons in rats [92–94]. HIV-1 Nef is another viral protein disturbing the dopamine functions, reducing striatal dopamine levels in HIV-1 mice. The animal will consequently develop mania-like behaviors and present a reduced content of dopamine and DAT [95].

HIV+ subjects present a diminished motor performance at multitasking and a decreased velocity compared to the control group. This may affect the daily life and require more attention to every motor task [96]. A psychomotor slowing of HIV patients was already described in early neuropsychological studies [97], which was presumed to be from the frontostriatal origin. The first hypothesis for the gait and balance problems was a neuropathy of the peripheral nervous system [98, 99]. However, the cerebellum, and the pons more exactly, is also implicated in HIV infection [100–105].

There is evidence of cerebellar damage [105–107] and an important degeneration of the cerebellar granular cell layer and axonal swelling. CT and MRI show pontocerebellar damage in HIV infection [108] and 3–6% of an HIV-infected group [109]. Men and women show tissue volume deficits in combined pons, vermis tissue, and cerebellar hemispheres. This will result in a deficit in motor performance like static postural stability, and tandem walking, particularly when the patients have their eyes closed during the test. The psychomotor speed and the finger dexterity were also impaired.

The pediatric HIV-1 infection will present different complications, involving deep abnormalities in the striatal dopamine system including the basal ganglia. The HIV-infected children present a slower-than-normal information processing and poor attentional abilities [110–112].
