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HIV-positive participants had worse complex motor performance than HIV-negative participants
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"Repetitive re-seeding of the CNS compartment by HIV over a longer period in older individuals may increase the size of the CNS reservoir, raising the probability of autonomous CNS infection and associated neurocognitive impairment.” AIDS 2004: 18;27-34. HNRC Group
ATIs may or are likely to increase & reestablish if reduced to undetectable CSF viral loads, which may or may not in the short term not cause detectable neurologic affects, but perhaps once resetablished or increased never disappear & may remain forever, we just do not know. These elements have NOT been considered in cure research & its potential harm regarding ATIs.
Immunosenescence is not discussed in this paper and IS associated with reduced immunity and this I think also affects brain function. This study finds 15% of affect on brain motor performance is caused by inflammation. I maintain the other 85% is due to direct affects of HIV & CSF RNA on the brain, and immune depletion & immunosenescense.
Jules
"HIV caused a decrease in activity during cue processing in the ventral striatum, with normal cortical functioning during reward outcome processing. Our results therefore suggest that HIV not only has an impact on fronto-striatal systems involved in executive functioning, but also has a direct impact on the function of the ventral-striatal reward system.
Pdf attached too
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.....Complex motor skills refer to a combination of cognitive and perceptual motor abilities, including perception, planning, continuous tracking, and sequential movements.6 Although the prevalence of complex motor impairment has receded in comparison with the pre-cART era, deficits in complex motor functioning are still observed in approximately 30% of those with HAND. Our sample consisted of virally suppressed, chronic HIV-positive patients; however, impairment in complex motor skills was still observed among 20% of the HIV-positive sample. This observed impairment rate is consistent with motor impairment rates (eg, 19%-25%) reported in previous literature.33 Some evidence indicates a higher impairment rate in complex motor performance among persons with chronic HIV compared to persons with acute or early HIV infection,34 which may reflect a history of immunosuppression and/or greater inflammation burden. For example, persons with AIDS performed significantly worse on a fine motor speed test than those without AIDS.35 Deficits in motor skills may indicate injury to the basal ganglia, which are part of the motor control pathways.36 The basal ganglia seem to be particularly vulnerable to alterations in blood-brain barrier permeability,37,38 immune cellular infiltration,39 and accumulation of HIV viral RNA.40 Neuropathological studies have observed higher concentrations of macrophages, microglia, and viral proteins in the basal ganglia.41
"HIV serostatus was also associated with poorer complex motor performance....On average, participants were non-Hispanic white (62.5%) men (78.3%) with some college education [mean 14.6 (SD 2.3) years of formal education]. Compared to the HIV-negative group, the HIV-positive group had fewer years of education, a greater proportion of males, and a greater proportion of individuals with medical comorbidities, MDD, and lifetime substance use disorders (P's < 0.05; Table 1).
Among the HIV-positive participants, 60% had an AIDS diagnosis, median estimated duration of HIV infection was 18.5 years, median current CD4+ T-cell count was 629 cells/mm3, and median nadir CD4+ T-cell count was 183 cells/mm3. HIV disease characteristics did not differ by age decade (P's > 0.05; Table 2), with the exception of duration of HIV infection and duration of exposure to ART, which were longer for each increasing age decade (P's < 0.01)
......In summary, HIV has a deleterious impact on complex motor skills, which may be partially explained by inflammatory processes.....Our sample consisted of virally suppressed, chronic HIV-positive patients; however, impairment in complex motor skills was still observed among 20% of the HIV-positive sample. Although some brain metabolite abnormalities may improve after initiating cART,51 some abnormalities persist, including ongoing inflammatory processes.52 A long-term prospective cohort study found interacting effects of aging and HIV disease stage, such that the magnitude of motor performance impairment was greater than the sum of the independent effects of age and HIV disease stage.7 The interaction between aging and HIV disease stage suggest that complex motor skills may be particularly susceptible to aging-related progression of neurocognitive impairment among HIV-positive adults. The Grooved Pegboard Test seems to be particularly sensitive to detecting neurocognitive decline among HIV-positive persons......A greater proportion of the HIV-positive group had global neurocognitive impairment (41.1%) compared with the HIV-negative group (25.5%; P = 0.02; odds ratio = 2.04). Composite inflammation burden scores were higher among participants with global neurocognitive impairment [mean = 2.0 (SD 1.4)] compared to those without impairment [mean = 1.5 (SD 1.2), P = 0.02; Hedges g = 0.38]. Finally, we examined whether other neurocognitive domains (ie, recall, executive functions, learning, verbal, working memory, and speed of information processing) would show similar associations with the composite inflammation burden score. After controlling for FDR using the BH method, only the complex motor domain showed a statistically significant association with the composite inflammation burden score.....Of the 5 individual inflammation biomarkers, the HIV serostatus groups differed on levels of MCP-1, sCD14, and TNF-a, which were higher in the HIV-positive group (P's < 0.05; Table 3). The HIV-positive group had a higher average composite inflammation burden score than the HIV-negative group
Some evidence indicates a higher impairment rate in complex motor performance among persons with chronic HIV compared to persons with acute or early HIV infection,34 which may reflect a history of immunosuppression and/or greater inflammation burden. Deficits in motor skills may indicate injury to the basal ganglia, which are part of the motor control pathways.36 The basal ganglia seem to be particularly vulnerable to alterations in blood-brain barrier permeability,37,38 immune cellular infiltration,39 and accumulation of HIV viral RNA. HIV was observed to have both direct and indirect effects through inflammation burden on complex motor performance; however, inflammation burden only accounted for 15.1% of the effect of HIV on complex motor performance. These results suggest there are additional mechanisms by which HIV may have deleterious effects on complex motor performance. Other factors contributing to neurocognitive impairment may include vascular remodeling (eg, pathological angiogenesis),48 metabolic disorders (eg, diabetes mellitus and visceral adiposity),49 and coinfections.
INTRODUCTION: Successful viral suppression from combination antiretroviral therapy (cART) has led to an increase in life expectancy among persons living with HIV (HIV-positive). Although severe HIV-associated neurocognitive disorder (HAND) is less prevalent in the cART era, mild to moderate HAND persists despite virologic suppression. HAND affects up to 50% of HIV-positive persons,1,2 with older HIV-positive adults at 1.5-3 times greater risk of neurocognitive impairment than their younger counterparts.3-5
Among neurocognitive domains affected by HAND, complex motor skills are consistently compromised across time. Complex motor skills refer to a combination of cognitive and perceptual motor abilities, including perception, planning, continuous tracking, and sequential movements.6 Although the prevalence of complex motor impairment has receded in comparison with the pre-cART era, deficits in complex motor functioning are still observed in approximately 30% of those with HAND.2 Complex motor impairment is related to everyday functioning impairment, including driving ability, highlighting the clinical relevance in understanding mechanistic pathways underlying HIV-associated motor dysfunction.6 A recent longitudinal study found that complex motor function is particularly vulnerable to the effects of age and stage of HIV infection, and implicated the basal ganglia as a neural correlate of interest.7 The effects of acute HIV infection on the basal ganglia are well documented,8 with greater atrophy associated with psychomotor slowing.9
Inflammation is one putative factor that may contribute to central nervous system (CNS) injury, including deficits in complex motor skills. Biomarkers of inflammation, such as cytokines and monocytes, are elevated in the context of HIV infection. HIV, viral products, and activated immune cells are able to cross the blood-brain barrier and contribute to inflammation in the CNS.10 Neuroimaging studies have shown that peripheral inflammatory biomarkers are able to alter neural activity in the basal ganglia, including dopaminergic activity, which is reflected by psychomotor slowing in HIV-negative adults.11 Among HIV-positive persons, global neurocognitive impairment is associated with elevation of various peripheral biomarkers of inflammation and coagulation (eg, cytokines,12 monocytes,13,14 and d-dimer15).
Taken together, deficits in complex motor performance are commonly observed among HIV-positive persons, and elevation in peripheral biomarkers of inflammation may be a contributing factor. Thus, we hypothesize that HIV will have negative direct and indirect effects through inflammation on complex motor performance."
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Inflammation Relates to Poorer Complex Motor Performance Among Adults Living With HIV on Suppressive Antiretroviral Therapy
Montoya, Jessica L., PhD*; Campbell, Laura M., BS; Paolillo, Emily W., MS; Ellis, Ronald J., MD, PhD; Letendre, Scott L., MD; Jeste, Dilip V., MD*,,; Moore, David J., PhD*
Jan 1 2019 JAIDS
Background: Inflammatory processes have been suggested to underlie early neurologic abnormalities among persons living with HIV (HIV-positive), such as deficits in complex motor function, that are purported to remit with effective antiretroviral therapy (ART). We hypothesized that HIV will have negative direct and indirect effects through inflammation on complex motor performance.
Methods: The sample consisted of 90 ART-treated virally suppressed HIV-positive and 94 HIV-negative adults, aged 36-65 years, with balanced recruiting in each age decade (36-45, 46-55, and 56-65). Biomarkers of inflammation (d-dimer, IL-6, MCP-1/CCL2, sCD14, and TNF-α) were measured, and a composite inflammation burden score was calculated. Complex motor performance was evaluated using the Grooved Pegboard Test.
Results: The HIV-positive group had worse complex motor performance (P = 0.001; Hedges g = -0.49) and a higher average inflammation burden composite score (P < 0.001; Hedges g = 0.78) than the HIV-negative group. Path analyses indicated that the indirect effect of HIV disease on complex motor performance through inflammation burden was statistically significant, accounting for 15.1% of the effect of HIV on complex motor performance.
Conclusions: Although neurologic findings (eg, deficits in motor speed/dexterity) commonly associated with HIV infection typically remit with ART, our analysis indicates that inflammation plays an important role in worse complex motor skills among HIV-positive adults. Future studies of strategies for managing chronic inflammation in HIV should consider using an inflammation burden composite and examining its effect on complex motor performance.
DISCUSSION
Although neurologic findings commonly associated with HIV infection have been suggested to largely remit with initiation of cART, our cross-sectional study observed worse complex motor skills across the adult age continuum of HIV-positive, relative to HIV-negative, adults. Inflammation burden was higher among HIV-positive adults, compared with the HIV-negative comparison group. Consistent with our hypothesis, HIV infection was observed to have both direct and indirect effects through inflammation on complex motor performance, such that inflammation burden accounted for 15.1% of the effect of HIV infection on motor performance when controlling for relevant covariates. These results indicate that inflammatory processes may contribute to worse complex motor skills in the context of cART-treated HIV.
Our sample consisted of virally suppressed, chronic HIV-positive patients; however, impairment in complex motor skills was still observed among 20% of the HIV-positive sample. This observed impairment rate is consistent with motor impairment rates (eg, 19%-25%) reported in previous literature.33 Some evidence indicates a higher impairment rate in complex motor performance among persons with chronic HIV compared to persons with acute or early HIV infection,34 which may reflect a history of immunosuppression and/or greater inflammation burden. For example, persons with AIDS performed significantly worse on a fine motor speed test than those without AIDS.35 Deficits in motor skills may indicate injury to the basal ganglia, which are part of the motor control pathways.36 The basal ganglia seem to be particularly vulnerable to alterations in blood-brain barrier permeability,37,38 immune cellular infiltration,39 and accumulation of HIV viral RNA.40 Neuropathological studies have observed higher concentrations of macrophages, microglia, and viral proteins in the basal ganglia.41
Our path analyses indicate that inflammation burden may play a role in the association between HIV infection and worse complex motorperformance. This finding is consistent with previous research demonstrating the detrimental impact of HIV and its proteins on the brain through peripheral and CNS pathways.10 Monocytes and macrophages are observed to infiltrate the CNS in HIV infection.10 Elevations in soluble markers of monocyte and cytokine activation, including sCD14, MCP-1/CCL2, and IL-6, have been observed among HIV-positive adults with neurocognitive impairment.42-44 Expression of MCP-1/CCL2 may contribute to upregulation of HIV-1 replication, thereby contributing to an increased risk of neurocognitive impairment.45 In addition to inflammation, coagulation imbalance, which includes upregulation of d-dimer, is associated with global neurocognitive functioning among HIV-positive adults.15 In the current analysis, d-dimer was included in the inflammation burden composite, given the bidirectional relationship between inflammation and coagulation (ie, coagulation imbalance is considered to be both a consequence of inflammation and an amplifier of the inflammatory response46). Multiple factors likely contribute to activation of inflammatory and coagulation pathways observed among HIV-positive persons on cART, such as viral replication, excess levels of translocated microbial products and other chronic pathogens (eg, cytomegalovirus), and loss of immunoregulatory responses.47
HIV was observed to have both direct and indirect effects through inflammation burden on complex motor performance; however, inflammation burden only accounted for 15.1% of the effect of HIV on complex motor performance. These results suggest there are additional mechanisms by which HIV may have deleterious effects on complex motor performance. Other factors contributing to neurocognitive impairment may include vascular remodeling (eg, pathological angiogenesis),48 metabolic disorders (eg, diabetes mellitus and visceral adiposity),49 and coinfections.50 This study evaluated a model that identified one plausible indirect pathway between HIV and worse complex motor performance; future research may build on this work by evaluating models with multiple pathways to estimate the relative contribution of various plausible mediators. A better understanding of the interplay of factors contributing to neurologic dysfunction in HIV may lead to more accurate prognosis and and/or risk stratification of HIV-positive adults in regard to neurologic dysfunction.
Although some brain metabolite abnormalities may improve after initiating cART,51 some abnormalities persist, including ongoing inflammatory processes.52 A long-term prospective cohort study found interacting effects of aging and HIV disease stage, such that the magnitude of motor performance impairment was greater than the sum of the independent effects of age and HIV disease stage.7 The interaction between aging and HIV disease stage suggest that complex motor skills may be particularly susceptible to aging-related progression of neurocognitive impairment among HIV-positive adults. The Grooved Pegboard Test seems to be particularly sensitive to detecting neurocognitive decline among HIV-positive persons.53
Our study findings should be considered in light of its limitations. First, although we used path analysis, this study was cross-sectional in nature, which precludes us from making inferences in regard to causation or mediation. Our results are also consistent with the alternative hypothesis that both inflammatory processes and complex motor skills may be mediated by an unobserved third variable. Given that the parent study involves repeated assessment of neurocognitive functioning and inflammation over 5 years, future analyses will examine whether changes in inflammation are associated with changes in complex motor functioning. Second, our study did not collect data on conditions (eg, hand arthritis, persistent traumatic hand injury, and peripheral neuropathy) that may confound interpretation of complex motor performance. Third, it is unclear how to best conceptualize inflammation burden because normative standards regarding biomarker measurement and conceptualization have not been established. However, our calculation of a composite inflammation burden score may be a viable method compared with reliance on a single biomarker, given our analysis indicated that complex motor performance was significantly associated with the composite but not any individual biomarker. Furthermore, conceptualization of an inflammation burden composite adds to the body of research aimed at developing clinically relevant risk indices (eg, Veterans Aging Cohort Index54). Fourth, our HIV-negative comparison group was relatively healthy and differed from the HIV-positive group on multiple characteristics. Fifth, our HIV-positive group consisted of mostly non-Hispanic white males with some college education, which is not fully representative of HIV-positive persons in the United States. Sixth, previous research indicates multitasks may better detect motor impairment compared with a single motor task (ie, finger tapping)55; the Grooved Pegboard Test, however, involves the use of many complex operations and is correlated with a range of cognitive functions.19
In summary, HIV has a deleterious impact on complex motor skills, which may be partially explained by inflammatory processes. Future studies of strategies for managing chronic inflammation in HIV may consider using an inflammation burden composite and examining how changes in inflammation burden affect complex motor performance, given the fact that this neurocognitive domain seems to be more strongly associated with inflammation relative to other domains.
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