HIV相关神经认知障碍：发病机制、诊断、治疗新进展

在抗反转录病毒治疗时代,尽管HIV相关神经认知障碍(HIV associated neurocognitive disorder,HAND)的发病时间似乎有了延迟,发病率和严重程度也都有所降低,但对于HIV感染者来说,仍是一种严重的并发症.根据现有的Frascati标准,HAND被分为3类:无症状性神经认知损害、轻度神经认知紊乱及HIV相关痴呆症.HAND的发病机制涉及宿主和病毒之间的诸多因素.当前HAND的诊断标准参差不齐,且没有明确的治疗药物.本文对当前HAND的发病机制、诊断、治疗等方面进行总结,以期为未来HAND的研究提供参考和新思路.     

Neurocognitive Disorders in Aging: A Primer on DSM-5 Changes and Framework for Application to Practice

Cognitive screening and brief cognitive assessment is an important skill for practitioners across gerontology disciplines. Results of such screening can then point to possible referral points for additional assessment and treatment. The recently released DSM-5 diagnostic criteria for neurocognitive disorders provide a new context for interpreting screening and incorporate many changes from the previous edition—including an increased reliance on cognitive assessment. In this article we first describe these changes from DSM-IV to DSM-5. Next we link these changes to the practice of cognitive screening and brief cognitive assessment. We then describe how cognitive screening can be embedded in an assessment framework that includes attention to symptom expression, normal aging, medical and psychiatric comorbidities, and base rates. It is increasingly likely that gerontology healthcare practitioners will encounter neurocognitive compromise in their practice. Thus, clinical care should incorporate services including cognitive screening and assessment, broad based differential diagnosis considering DSM-5, and appropriate referral.     

Screening for HIV-related neurocognitive impairment in clinical practice: Challenges and opportunities

With increasingly successful management of HIV, focus has shifted away from AIDS-related complications to other chronic co-morbidities. For HIV-related cognitive problems, the true aetiopathogenesis and epidemiology remains unclear. Rather than a systematic review, this paper presents the challenges and the opportunities we faced in establishing our own clinical service. Papers were identified using Pubmed and the terms “screening”, “HIV” and “neurocognitive”. This article covers the background of HIV-associated neurocognitive disorders (HAND) with a focus on HIV-related neurocognitive impairment (NCI), detailing classification, prevalence, diagnostic categories and diagnostic uncertainties. Screening is discussed, including a comparison of the available screening tools for cognitive deficits in HIV-infected patients and the importance of practice effects. Discussed also are the normal ranges and the lack thereof and potential investigations for those found to have impairments. We conclude by discussing the role of NCI screening in routine clinical care at the current time.     

Computerized testing augments pencil-and-paper tasks in measuring HIV-associated mild cognitive impairment(*)

Background

Existing tools for rapid cognitive assessment in HIV‐positive individuals with mild cognitive deficits lack sensitivity or do not meet psychometric requirements for tracking changes in cognitive ability over time.

Methods

Seventy‐five nondemented HIV‐positive patients were evaluated with the Montreal Cognitive Assessment (MoCA), a brief battery of standardized neuropsychological tests, and computerized tasks evaluating frontal‐executive function and processing speed. Rasch analyses were applied to the MoCA data set and subsequently to the full set of data from all tests.

Results

The MoCA was found to adequately measure cognitive ability as a single, global construct in this HIV‐positive cohort, although it showed poorer precision for measuring patients of higher ability. Combining the additional tests with the MoCA resulted in a battery with better psychometric properties that also better targeted the range of abilities in this cohort.

Conclusion

This application of modern test development techniques shows a path towards a quick, quantitative, global approach to cognitive assessment with promise both for initial detection and for longitudinal follow‐up of cognitive impairment in patients with HIV infection.     

HIV Antiretroviral Medication Neuropenetrance and Neurocognitive Outcomes in HIV+ Adults: A Review of the Literature Examining the Central Nervous System Penetration Effectiveness Score

This literature review summarizes the existing research examining the CNS penetration effectiveness (CPE) score and neurocognitive outcomes (i.e., neuropsychological assessment and neurocognitive screening) in HIV+ individuals. Despite the effectiveness of Combined Antiretroviral Therapy (CART) in reducing mortality and morbidity in HIV and controlling viral replication, HIV often persists in the Central Nervous System (CNS), and rates of neurocognitive impairment remain higher than predicted in the post-CART era. The CPE score was developed to rank antiretroviral regimens on their ability to penetrate the CNS and potency in inhibiting the virus, and it has been examined in relation to neurocognitive functioning for over a decade. Based on the results of 23 studies, we conclude that CPE is not as strongly associated with neurocognitive outcomes as initially hypothesized, although higher CPE ARV regimens may be associated with modest, improved outcomes in global neurocognitive functioning, and to a lesser extent attention/working memory and learning/memory. Conclusions, however, are limited by the heterogeneity in study design and methods, and the lack of a more recent CPE metric update. It is recommended that future research in this area employ comprehensive, standardized neuropsychological test batteries and examine domain-level performance, and use the newer 2010 CPE metric, although an updated CPE ranking is urgently needed.     

One for all,all for one: neuro-HIV multidisciplinary platform for the assessment and management of neurocognitive complaints in people living with HIV

Background

With ageing, comorbidities such as neurocognitive impairment increase among people living with HIV (PLWH). However, addressing its multifactorial nature is time-consuming and logistically demanding. We developed a neuro-HIV clinic able to assess these complaints in 8 h using a multidisciplinary approach.

Methods

People living with HIV with neurocognitive complaints were referred from outpatient clinics to Lausanne University Hospital. Over 8 h participants underwent formal infectious disease, neurological, neuropsychological and psychiatric evaluations, with opt-out magnetic resonance imaging (MRI) and lumbar puncture. A multidisciplinary panel discussion was performed afterwards, with a final report weighing all findings being produced.

Results

Between 2011 and 2019, a total of 185 PLWH (median age 54 years) were evaluated. Of these, 37 (27%) had HIV-associated neurocognitive impairment, but they were mainly asymptomatic (24/37, 64.9%). Most participants had non-HIV-associated neurocognitive impairment (NHNCI), and depression was prevalent across all participants (102/185, 79.5%). Executive function was the principal neurocognitive domain affected among both groups (75.5% and 83.8% of participants impaired, respectively). Polyneuropathy was found in 29 (15.7%) participants. Abnormalities in MRI were found in 45/167 participants (26.9%), being more common among NHNCI (35, 77.8%), and HIV-1 RNA viral escape was detected in 16/142 participants (11.2%). Plasma HIV-RNA was detectable in 18.4% out of 185 participants.

Conclusions

Cognitive complaints remain an important problem among PLWH. Individual assessment from a general practitioner or HIV specialist is not enough. Our observations show the many layers of HIV management and suggest that a multidisciplinary approach could be helpful in determining non-HIV causes of NCI. A 1-day evaluation system is beneficial for both participants and referring physicians.     

Synergistic Impairment of the Neurovascular Unit by HIV-1 Infection and Methamphetamine Use: Implications for HIV-1-Associated Neurocognitive Disorders

The neurovascular units (NVU) are the minimal functional units of the blood–brain barrier (BBB), composed of endothelial cells, pericytes, astrocytes, microglia, neurons, and the basement membrane. The BBB serves as an important interface for immune communication between the brain and peripheral circulation. Disruption of the NVU by the human immunodeficiency virus-1 (HIV-1) induces dysfunction of the BBB and triggers inflammatory responses, which can lead to the development of neurocognitive impairments collectively known as HIV-1-associated neurocognitive disorders (HAND). Methamphetamine (METH) use disorder is a frequent comorbidity among individuals infected with HIV-1. METH use may be associated not only with rapid HIV-1 disease progression but also with accelerated onset and increased severity of HAND. However, the molecular mechanisms of METH-induced neuronal injury and cognitive impairment in the context of HIV-1 infection are poorly understood. In this review, we summarize recent progress in the signaling pathways mediating synergistic impairment of the BBB and neuronal injury induced by METH and HIV-1, potentially accelerating the onset or severity of HAND in HIV-1-positive METH abusers. We also discuss potential therapies to limit neuroinflammation and NVU damage in HIV-1-infected METH abusers.     

Depression and neurocognitive performance in individuals with HIV/AIDS: 2-year follow-up

OBJECTIVES: The aims of this study were to follow a cohort of HIV-infected individuals for 2 years to assess changes in depression and neuropsychological performance over time, to explore the relationship between depression, HIV illness and neuropsychological performance, and to examine the natural history of the effect of highly active antiretroviral therapy (HAART) on depression and neurocognitive performance. METHODS: HIV-seropositive out-patients were assessed at baseline and at 2-year follow-up. At each assessment, patients were assessed for depression [using the Beck Depression Inventory (BDI) and Structured Clinical Interview (SCID-CV)] and completed a battery of neuropsychological tests including the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the Hopkins HIV Dementia Scale (HDS). RESULTS: At baseline, 34.8% scored > or =14 on the BDI [> or =14 suggests depressive symptoms (DS)]. The SCID-CV revealed that 27% of participants met the criteria for current mood disorder. Seven per cent of the participants' scores on the HDS indicated HIV-associated cognitive changes. Eighty participants were re-tested at 2-year follow-up and were split into two groups based on BDI scores at baseline. CANTAB results revealed that the cohort were significantly impaired on nine of 10 measures compared with age-matched normative data. Neurocognitive performance significantly improved for participants with no DS at baseline, whereas participants with DS at baseline did not show as much improvement. Multivariate analysis revealed that 40% of the change in cognitive performance was attributable to the variables age, AIDS and HAART regimen. CONCLUSION: These results suggest a significant decline in depression scores and an improvement in several neurocognitive domains over time, with a relationship between HIV illness, HAART, symptoms of depression and neurocognitive performance.     

Investigation of combined treatment of acupuncture and neurofeedback for improving cognitive function in mild neurocognitive disorder: A randomized,assessor-blind,pilot study

Background:Mild neurocognitive disorder (MND) is an intermediate state that can progress to dementia, and the cognitive reserve of MND is an important task in preventing dementia. Acupuncture and neurofeedback (NF) training have been used to improve cognitive function and treat MND or dementia, but their effectiveness remains controversial. In this trial, we will evaluate the efficacy and safety of combined NF-acupuncture treatment in comparison with single acupuncture treatment.Methods and design:This study is a randomized, assessor-blind, pilot trial. It is designed in accordance with the Standards for Reporting Interventions in Controlled Trials of Acupuncture. A total of 44 MND participants who meet the inclusion and exclusion criteria will be enrolled, and each will be randomly assigned to 1 of 2 groups of 22 subjects. Each subject will visit 24 times over 12 weeks and receive either acupuncture or NF-acupuncture combined treatment. At visit 25 (week 13), a follow-up evaluation will be performed, and then the investigator will analyze the results. The primary outcome is defined by the Korean version of the Montreal Cognitive Assessment score from screening to visit 25. The secondary outcome includes the following: change in Alzheimer Disease Assessment Scale–Cognitive, the Korean version of the Beck Depression Inventory, Body Awareness Questionnaire, delayed matching to sample task scores, and functional near-infrared spectroscopy values, from visit 1 to visit 25; heart rate variability values from visit 1 to visit 5, visit 9, visit 13, visit 21, visit 25; breath per minute values from visit 1 to visit 1 to 25.Discussion:We will evaluate the effectiveness and safety of combined NF-acupuncture therapy, and expect that it will serve as the basis for the use of NF together with acupuncture in the clinical setting.Trial registration number:KCT0004972 (registered in Clinical Research Information Service of the Republic of Korea, https://cris.nih.go.kr/cris/search/detailSearch.do/16239)     

HIV and STI knowledge,testing, and risk among adult crack users in Mexico city: baseline findings from a feasibility study

Recent research has documented crack cocaine’s increasing spread in Mexico, which is likely to contribute to the rapid transmission of HIV and other sexually transmitted infections (STIs). In Mexico, crack use is increasing most rapidly in vulnerable, hard-to-reach populations, where little is known about risk behaviors. This report aims to present baseline data regarding HIV and STI knowledge and testing prevalence from an innovative projection mapping HIV intervention, in which 3-D illusions, animation, and visual text graphics and sound are projected onto buildings with health messages that were designed to disrupt everyday life and connect with the target population. Fifty-eight men and women who used crack in the past month without receiving drug treatment were recruited and interviewed before the projection mapping intervention took place. Testing instruments included a sociodemographic assessment, drug use and treatment profile, HIV and STI knowledge questionnaires, and a sex and drug risk assessment. The mean scores for respondents on the HIV Knowledge Questionnaire (10.5 out of 18, 58.3%) and STD Knowledge Questionnaire (9.5 out of 27, 35.2%) were both low. Respondents also reported high rates of sexual risk behaviors, with 73% reporting never using a condom and 64% never being tested for HIV. This report provides a portrait of STI and HIV risk among a vulnerable population in Mexico City and the need for urgent interventions to prevent the spread of STIs and HIV. The associated projection mapping intervention will seek to increase HIV and STI knowledge and reduce risk in this hard-to-reach population.     

Cohort profile: the German ClinSurv HIV project--a multicentre open clinical cohort study supplementing national HIV surveillance

Background

New forms of HIV/AIDS therapy require new surveillance instruments to meet shifting public health demands. The Clinical Surveillance of HIV Disease (ClinSurv HIV) project was established in 1999 as a collaboration between major HIV treatment centres in Germany and the Robert Koch Institute (RKI). The project contributes to national HIV surveillance and focuses on the changing epidemiology of HIV/AIDS after the introduction of new therapies in 1995.

Methods

ClinSurv HIV is designed as an open multicentre observational cohort study of HIV‐infected patients. Anonymized data on diagnoses, treatment and laboratory parameters are collected in a standardized format. Data are currently sampled biannually via 11 centres specializing in HIV diagnosis and care within the legal framework of the German Protection against Infection Act [Infektionsschutzgesetz (IfSG)].

Results

A total of 14 874 patients were enrolled in the study by 30 June 2009. Of these, 10 221 patients (68.7%) were enrolled after 1 January 1999 and 6006 patients (40.4%) were known to have been diagnosed as positive for HIV before 1999. Evaluation indicators, such as the number of newly enrolled patients per half‐year period, loss to follow‐up, completeness of data per case, availability of data per possible clinical contact, and internal quality control parameters, show a very stable evolution in the cohort, which although open, can be observed. Comparison with the national HIV surveillance data suggests a high degree of representativeness according to major demographic variables.

Conclusion

Bearing in mind the obvious strengths and weaknesses discussed, the German ClinSurv HIV cohort provides a broad range of research opportunities in the field of HIV/AIDS both within Germany and in international collaborative research.