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| {{HIV}}
| | #REDIRECT[[AIDS natural history, complications, and prognosis#Cognitive impairment in HIV]] |
| {{CMG}}
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| ==Overview==
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| HIV enters the brain early on in the infection.<ref name=Avison>{{Citation |last1= Avison |first1=MJ|last2= Nath |first2=A|last3= Greene-Avison |first3=R|last4= Schmitt |first4=FA|last5= Greenberg |first5=RN|last6= Berger |first6=JR|title = Neuroimaging correlates of HIV-associated BBB compromise | journal = Journal of Neuroimmunology | volume = 157| issue = 1–2| pages = 140–146 | year = 2004| pmid = 15579291 | doi =10.1016/j.jneuroim.2004.08.025 }}</ref> It is thought that [[HIV]] uses a “Trojan horse” 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.<ref name=Berger>{{Citation |last1= Berger |first1=JR|last2= Avison |first2= MJ | title = The Blood Brain Barrier in HIV Infection | journal = Frontiers in Bioscience | volume = 9| issue = | pages = 2680–2685 | year = 2004| pmid = 15358591 | doi =10.2741/1427 }}</ref> 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.<ref name=Gonzalez>{{Citation |last1= Gonzalez-Scarano |first1=F|last2= Martin-Garcia |first2=J| title = The neuropathogenesis of AIDS | journal = Nature Reviews Immunology | volume = 5| issue = 1| pages = 69–81 | year = 2005| pmid = 15630430 | doi =10.1038/nri1527 }}</ref> 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.<ref name=Eugenin>{{Citation | last = Eugenin | first = EA | last2 = Clements | first2 = JE | last3 = Zink | first3 = MC | last4 = Berman | first4 = JW | title = Human Immunodeficiency Virus Infection of Human Astrocytes Disrupts Blood-Brain Barrier Integrity by a Gap Junction-Dependent Mechanism | journal = Journal of Neuroscience | volume = | 31 issue = 26| pages = 9456–9465 | year = 2011 | pmid = 21715610 | issue = 26 | pmc = 3132881 }}</ref>
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| ==Anatomical areas involved==
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| *HIV is associated with pathological changes in mainly subcortical and fronto-striatal areas of the brain, including the [[basal ganglia]], deep white matter, and [[hippocampus|hippocampal]] regions.
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| *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]].<ref name = Castelo1>{{Citation |last1= Castelo |first1= JMB |last2= Courtney |first2= MG |last3= Melrose |first3= RJ |last4= Stern |first4= CE | title = Putamen hypertrophy in nondemented patients with human immunodeficiency virus infection and cognitive impairments | journal = Archives of Neurology | volume = 64| issue = 9| pages = 1275–1280 | year = 2007 | pmid = 17846265 | doi =10.1001/archneur.64.9.1275 }}</ref>
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| *Some studies suggest loss of brain volume in cortical and subcortical regions even in asymptomatic HIV patients and patients who were on stable treatment.<ref name=Cohen/> 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 present with greater cerebral atrophy.<ref name=Cohen>{{Citation | last1 = Cohen | first1 = RA | last2 = Harezlak | first2 = J | last3 = Schifitto | first3 = G | last4 = Hana | first4 = G | last5 = Clark | first5 = U | last6 = Gongvatana | first6 = A | last7 = Paul | first7 = R | last8 = Taylor | first8 = M | last9 = Thompson | first9 = P | display-authors = 2 | title = Effects of nadir CD4 count and duration of human immunodeficiency virus infection on brain volumes in highly active antiretroviral therapy era | journal = Journal of Neurovirology | volume = 16 | issue = 1 | pages = 25–32 | year = 1981 | pmid = 20113183 | doi = 10.3109/13550280903552420 | pmc = 2995252 }}</ref>
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| *CD4 lymphocyte counts have also been related to greater rates of brain tissue loss.<ref name=Cardena>{{Citation |last1= Cardenas |first1=VA|last2= Meyerhoff |first2=DJ|last3= Studholme |first3=C|last4= Kornak |first4=J|last5= Rothlind |first5=J|last6= Lampiris |first6=H|last7=Neuhaus |first7=J|last8= Grant |first8=RM|last9= Chao |first9=LL| title = Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy | journal = Journal of Neurovirology | volume = 15| issue = 4| pages = 324–333 | year = 2009| pmid = 19499454 | doi =10.1080/13550280902973960 |pmc= 2889153 }}</ref>
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| *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<ref name=Cohen/> and total white matter.<ref>{{Citation | last1 = Jernigan | first1 = TL| last2 = Archibald | first2 = SL |last3= Fennema-Notestine |first3=C|last4= Taylor |first4=MJ|last5= Theilmann |first5=RJ|last6= Julaton |first6=MD|last7= Notestine |first7=RJ|last8= Wolfson |first8=T|last9= Letendre |first9=SL| title = Clinical factors related to brain structure in HIV: the CHARTER study | journal = Journal of Neurovirology | volume = 17| issue = 3 | pages = 248–57| year = 2011| pmid = 21544705 | doi =10.1007/s13365-011-0032-7 }}</ref>
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| *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.<ref name=Wang>{{Citation |last1= Wang |first1=X|last2= Foryt |first2=P|last3= Ochs |first3=R|last4= Chung |first4=JH|last5=Wu|first5=Y|last6= Parris |first6=T|last7= Ragin |first7=A| title = Abnormalities in Resting-State Functional Connectivity in Early Human Immunodeficiency Virus Infection | journal = Brain Connectivity | volume = 1| issue = | pages = 208–217 | year = 2011 | pmid = | doi = }}</ref>
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| ==Behavioral aspects of neurocognitive Impairments==
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| *[[Cognition|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.<ref>{{Citation |last1= Castelo |first1= JMB |last2= Sherman |first2= SJ |last3= Courtney |first3= MG |last4= Melrose |first4=RJ|last5= Stern |first5=SE| title = Altered hippocampal-prefrontal activation in HIV patients during episodic memory encoding | journal = Neurology | volume = 66| issue = 11 | pages = 1688–1695 | year = 2006| pmid = 16769942 | doi =10.1212/01.wnl.0000218305.09183.70 }}</ref>
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| *Severity of impairment in different domains varies depending on whether or not a patient is being treated with [[antiretroviral drug|HAART or monotherapy]].<ref name=Cysique>{{Citation |last1= Cysique |first1= LA |last2= Maruff |first2=P|last3= Brew |first3=BJ| title = Prevalence and pattern of neuropsychological impairment in human immunodeficiency virus-infected/acquired immunodeficiency syndrome (HIV/AIDS) patients across pre-and post-highly active antiretroviral therapy eras: A combined study of two cohorts | journal = Journal of Neurovirology | volume = 10| issue = 6| pages = 350–357 | year = 2004| pmid = 15765806 | doi =10.1080/13550280490521078 }}</ref>
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| *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.<ref name = Bogdanova>{{Citation |last1= Bogdanova |first1=Y|last2= Diaz-Santos |first2=M|last3= Cronin-Golomb |first3=A| title = Neurocognitive correlates of alexithymia in asymptomatic individuals with HIV | journal = Neuropsychologia | volume = 48| issue = 5| pages = 1295–1304 | year = 2010 | pmid = 20036267 | doi =10.1016/j.neuropsychologia.2009.12.033 |pmc= 2843804 }}</ref><ref name=Oleson>{{Citation |last1= Olesen |first1=PJ|last2= Schendan |first2=HE|last3= Amick |first3=MM|last4= Cronin-Golomb |first4=A| title = HIV infection affects parietal-dependent spatial cognition: Evidence from mental rotation and hierarchical pattern perception | journal = Behavioral Neuroscience| volume = 121 | issue = 6|pages = 1163–1173 | year = 2007 | pmid = 18085869 | doi =10.1037/0735-7044.121.6.1163 }}</ref>
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| *In addition to cognitive impairments, psychological dysfunction is also noted. For example, patients with HIV have higher rates of [[major depressive disorder|clinical depression]] and [[alexithymia]], i.e., difficulty processing or recognizing one’s own emotions.<ref name=Bogdanova/> Patients also have more difficulty recognizing facial emotions.<ref name=Clark>{{Citation |last1= Clark |first1=US|last2= Cohen |first2=RA|last3= Westbrook |first3=ML|last4= Devlin |first4=KN|last5= Tashima |first5=KT|title = Facial emotion recognition impairments in individuals with HIV | journal = Journal of the International Neuropsychological Society | volume = 16 | issue = 6| pages = 1127–1137 | year = 2010 | pmid = 20961470 | doi =10.1017/S1355617710001037 |pmc= 3070304 }}</ref>
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| *Without combination antiretroviral therapy, cognitive impairments increase with successive stages of HIV.<ref name=Heaton>{{Citation |last1= Heaton |first1=RK|last2= Franklin |first2= DR |last3= Ellis |first3=RJ|last4= McCutchan |first4=JA|last5=Letendre|first5=SL|last6=Leblanc|first6=S|last7=Corkran|first7=SH|last8=Duarte|first8=NA|last9=Clifford|first9=DB| title = HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors | journal = Journal of Neurovirology | volume = 17 | issue = 1| pages = 3–16| year = 2010 | pmid = 21174240 | doi =10.1007/s13365-010-0006-1 |pmc= 3032197 }}</ref> HIV patients in early stages show mild difficulties in concentration and attention.<ref name = Ances>{{Citation | last = Ances | first = BM | last2 = Ellis | first2 = RJ | title = Dementia and neurocognitive disorders due to HIV-1 infection| journal = Seminars in Neurology| volume = 27 | issue = 1 | pages = 86–92 | year = 2007 | pmid = 17226745 | doi =10.1055/s-2006-956759 }}</ref> In advanced cases of HIV-associated dementia, speech delay, motor dysfunction, and impaired thought and behavior are observed.<ref name =Ances/> Specifically, lower motor speeds were found to correlate with hypertrophy of the right putamen.<ref name=Castelo1/>
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| *The diagnosis of HIV-associated neurocognitive impairment is made using clinical criteria after considering and ruling out other possible causes.<ref name=Ances/> 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.<ref name = Heaton/>
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| ==Reference==
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| {{reflist|2}}
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