Karl Goodkin

Prolonged Grief Disorder: Psychometric Validation of Criteria Proposed for DSM-V and ICD-11

Holly Prigerson and colleagues tested the psychometric validity of criteria for prolonged grief disorder (PGD) to enhance the detection and care of bereaved individuals at heightened risk of persistent distress and dysfunction.

Subcortical brain atrophy persists even in HAART-regulated HIV disease

The purpose of this study was to determine the pattern and extent of caudate nucleus and putamen atrophy in HIV-infected men with well-controlled immune status and viral replication. 155 men underwent structural brain magnetic resonance imaging; 84 were HIV-infected and 71 were uninfected controls. MRI data were processed using the Fully Deformable Segmentation routine, producing volumes for the right and left caudate nucleus and putamen, and 3-D maps of spatial patterns of thickness. There was significant atrophy in the HIV-infected men in both the caudate and putamen, principally in the anterior regions. The volume of the basal ganglia was inversely associated with the time since first seropositivity, suggesting that either there is a chronic, subclinical process that continues in spite of therapy, or that the extent of the initial insult caused the extent of atrophy.

Normative scores for a brief neuropsychological battery for the detection of HIV-associated neurocognitive disorder (HAND) among South Africans

BackgroundThere is an urgent need to more accurately diagnose HIV-associated neurocognitive disorder (HAND) in Africa. Rapid screening tests for HIV-associated dementia are of limited utility due to variable sensitivity and specificity. The use of selected neuropsychological tests is more appropriate, but norms for HIV seronegative people are not readily available for sub-Saharan African populations. We sought to derive normative scores for two commonly used neuropsychological tests that generate four test scores -- namely the Trail-Making Test (Parts A and B) and the Digit Span Test [Forward (DSF) and Backward (DSB)]. To assess memory and recall, we used the memory item of the International HIV Dementia Scale (IHDS).FindingsOne hundred and ten HIV seronegative participants were assessed at McCord Hospital, Durban, South Africa between March 3rd and October 31st, 2008. We excluded people with major depressive disorder, substance use abuse and dependence and head injuries (with or without loss of consciousness). All the participants in this study were African and predominantly female with an average age of 28.5 years and 10 years of education. Age and gender influenced neuropsychological functioning, with older people performing worse. The effect of gender was not uniform across all the tests.ConclusionThese two neuropsychological tests can be administered with the IHDS in busy antiretroviral clinics. Their performance can be measured against these norms to more accurately diagnose the spectrum and progression of HAND.

Mixed Membership Trajectory Models of Cognitive Impairment in the Multicenter AIDS Cohort Study

Objective:The longitudinal trajectories that individuals may take from a state of normal cognition to HIV-associated dementia are unknown. We applied a novel statistical methodology to identify trajectories to cognitive impairment, and factors that affected the ‘closeness’ of an individual to one of the canonical trajectories. Design:The Multicenter AIDS Cohort Study (MACS) is a four-site longitudinal study of the natural and treated history of HIV disease among gay and bisexual men. Methods:Using data from 3892 men (both HIV-infected and HIV-uninfected) enrolled in the neuropsychology substudy of the MACS, a Mixed Membership Trajectory Model (MMTM) was applied to capture the pathways from normal cognitive function to mild impairment to severe impairment. MMTMs allow the data to identify canonical pathways and to model the effects of risk factors on an individuals ‘closeness’ to these trajectories. Results:First, we identified three distinct trajectories to cognitive impairment: ‘normal aging’ (low probability of mild impairment until age 60); ‘premature aging’ (mild impairment starting at age 45–50); and ‘unhealthy’ (mild impairment in 20s and 30s) profiles. Second, clinically defined AIDS, and not simply HIV disease, was associated with closeness to the premature aging trajectory, and, third, hepatitis-C infection, depression, race, recruitment cohort and confounding conditions all affected individuals closeness to these trajectories. Conclusion:These results provide new insight into the natural history of cognitive dysfunction in HIV disease and provide evidence for a potential difference in the pathophysiology of the development of cognitive impairment based on trajectories to impairment.

Effect of ageing on neurocognitive function by stage of HIV infection: evidence from the Multicenter AIDS Cohort Study

BACKGROUND The demographics of the HIV epidemic in the USA have shifted towards older age. We aimed to establish the relationship between the processes of ageing and HIV infection in neurocognitive impairment. METHODS With longitudinal data from the Multicenter AIDS Cohort Study, a long-term prospective cohort study of the natural and treated history of HIV infection among men who have sex with men in the USA, we examined the effect of ageing, HIV infection (by disease stage), and their interaction on five neurocognitive domains: information processing speed, executive function, episodic memory, working memory, and motor function. We controlled for duration of serostatus in a subanalysis, as well as comorbidities and other factors that affect cognition. Analyses were by linear mixed models for longitudinal data. FINDINGS 5086 participants (47 886 visits) were included in the analytic sample (2278 HIV-seropositive participants contributed 20 477 visits and 2808 HIV-seronegative control participants contributed 27 409 visits). In an a-priori multivariate analysis with control variables including comorbidities and time since seroconversion, significant, direct negative effects of ageing were noted on all neurocognitive domains (p<0·0001 for all). Similar effects were noted for late-stage HIV disease progression on information processing speed (p=0·002), executive function (p<0·0001), motor function (p<0·0001), and working memory (p=0·001). Deleterious interaction effects were also noted in the domains of episodic memory (p=0·03) and motor function (p=0·02). INTERPRETATION A greater than expected effect of ageing on episodic memory and motor function with advanced stages of HIV infection suggests that these two domains are most susceptible to the progression of neurocognitive impairment caused by ageing in individuals with HIV. This deficit pattern suggests differential damage to the hippocampus and basal ganglia (specifically nigrostriatal pathways). Older individuals with HIV infection should be targeted for regular screening for HIV-associate neurocognitive disorder, particularly with tests referable to the episodic memory and motor domains. FUNDING National Institute of Mental Health.

Cortical brain atrophy and intra-individual variability in neuropsychological test performance in HIV disease

To characterize the relationship between dispersion-based intra-individual variability (IIVd) in neuropsychological test performance and brain volume among HIV seropositive and seronegative men and to determine the effects of cardiovascular risk and HIV infection on this relationship. Magnetic Resonance Imaging (MRI) was used to acquire high-resolution neuroanatomic data from 147 men age 50 and over, including 80 HIV seropositive (HIV+) and 67 seronegative controls (HIV-) in this cross-sectional cohort study. Voxel Based Morphometry was used to derive volumetric measurements at the level of the individual voxel. These brain structure maps were analyzed using Statistical Parametric Mapping (SPM2). IIVd was measured by computing intra-individual standard deviations (ISD’s) from the standardized performance scores of five neuropsychological tests: Wechsler Memory Scale-III Visual Reproduction I and II, Logical Memory I and II, Wechsler Adult Intelligence Scale-III Letter Number Sequencing. Total gray matter (GM) volume was inversely associated with IIVd. Among all subjects, IIVd -related GM atrophy was observed primarily in: 1) the inferior frontal gyrus bilaterally, the left inferior temporal gyrus extending to the supramarginal gyrus, spanning the lateral sulcus; 2) the right superior parietal lobule and intraparietal sulcus; and, 3) dorsal/ventral regions of the posterior section of the transverse temporal gyrus. HIV status, biological, and cardiovascular disease (CVD) variables were not linked to IIVd -related GM atrophy. IIVd in neuropsychological test performance may be a sensitive marker of cortical integrity in older adults, regardless of HIV infection status or CVD risk factors, and degree of intra-individual variability links with volume loss in specific cortical regions; independent of mean-level performance on neuropsychological tests.

Diagnostic utility of the HIV dementia scale and the international HIV dementia scale in screening for HIV-associated neurocognitive disorders among Spanish-speaking adults

ABSTRACT Given that neurocognitive impairment is a frequent complication of HIV-1 infection in Spanish-speaking adults, the limited number of studies assessing HIV-associated neurocognitive disorders (HAND) in this population raises serious clinical concern. In addition to being appropriately translated, instruments need to be modified, normed, and validated accordingly. The purpose of the current study was to examine the diagnostic utility of the HIV Dementia Scale (HDS) and International HIV Dementia Scale (IHDS) to screen for HAND in Spanish-speaking adults living with HIV infection. Participants were classified as either HAND (N = 47) or No-HAND (N = 53) after completing a comprehensive neuropsychological evaluation. Receiver operating characteristic analyses found the HDS (AUC = .706) was more sensitive to detecting HAND than the IHDS (AUC = .600). Optimal cutoff scores were 9.5 for the HDS (PPV = 65.2%, NPV = 71.4%) and 9.0 for the IHDS (PPV = 59.4%, NPV = 59.1%). Canonical Correlation Analysis found the HDS converged with attention and executive functioning. Findings suggest that while the IHDS may not be an appropriate screening instrument with this population, the HDS retains sufficient statistical validity and clinical utility to screen for HAND in Spanish-speaking adults as a time-efficient and cost-effective measure in clinical settings with limited resources.

Assessing the prevalence of HIV, HBV, and HCV infection among people with severe mental illness.

People with severe mental illness are at higher risk for HIV infection than the general population. Early studies in New York suggested that the prevalence of HIV infection among people with severe mental illness was variable, depending on factors such as homelessness, treatment setting and status, specifi c psychotic diagnosis, dual diagnosis with substance use disorders, and sampling method (open vs anonymous). General population risk factors for HIV infection also have their expected eff ects in people with severe mental illness, including high-risk sexual activity (among men who have sex with men, heterosexuals, or injection drug users), injection drug use, ethnicity, gender, age, and viral load at time of exposure. Additional factors directly related to severe mental illness are cognitive impairment and psychotic symptoms that impede the planned use of precautions for risk in sexual activity and injection drug use, which present special diffi culties to controlling HIV in this population. Thus, the effi cacy of antipsychotic treatment and adherence to treatment is relevant to the risk of blood-borne infections in people with severe mental illness. In The Lancet Psychiatry, Elisabeth Hughes and colleagues make a major contribution to this subject by examining the prevalences of HIV, hepatitis C virus, and hepatitis B virus infection simultaneously in patients with severe mental illness. They used a well-defi ned approach to identify relevant articles and to defi ne the studies by specifi c conditions of testing (although “AIDS” could have been added as a search term and AIDSLine as a database). They included people aged older than 15 years, diagnosed with severe mental illness, and treated in a psychiatric setting. Studies in which prevalence data were obtained only from case notes, self-report, or the grey literature were excluded. They determined the eligibility of studies by a consensus strategy and used the Quality Assessment Tool for Systematic Reviews of Observational Studies to assess study quality. Hughes and colleagues modifi ed the tool to show whether participants were clearly defi ned as having severe mental illness (yes or no), participation rate (>60%=1, ≤60%=0), whether control variables were used (controlled=1, only descriptive=0), and sample size (≥200 participants=1, <200 participants=0), although the eff ects of these modifi cations on reliability and validity are not known. They did a meta-analysis to calculate combined estimates and 95% CIs for each continent. Logistic regression was done to allow for the proportions being unable to have values less than 0, and random eff ects were assumed because there was clear clinical heterogeneity among the samples. The 373 reports they found included 169 (45%) duplicates and they excluded 41 (11%) because the full-text was not available in English and 74 (20%) because they were deemed ineligible. With the addition of two papers from an updated search, the authors had 91 articles for assessment. This reduction might limit the generalisability of the fi ndings. HIV infection had the largest sample size and was the subject of the most studies: 44 studies assessed HIV (21 071 patients), 19 assessed hepatitis B virus (8163 patients), and 28 studies assessed hepatitis C virus (14 888 patients). Most of the HIV and hepatitis C virus studies were from the USA, and few were from Europe, although the investigators attempted to control for continent. Ultimately, the most important unit for analysis here might be number of studies rather than the cumulative number of participants across studies. Most studies used convenience samples from in-patient psychiatric treatment settings; yet, the studies show that data from patients who are not in treatment are needed to best approximate the entire population of patients with severe mental illness. It is also important to estimate the number of patients with severe mental illness who are dually diagnosed with substance use disorders to maximise generalisability, because blood-borne infections are much more common in this group. Another issue not addressed by Hughes and colleagues was the percentage of patients with dual and triple co-infections. Hepatitis C virus coinfection occurs in as many as 25% of patients with HIV in the USA. Worldwide, 10% of patients with HIV are coinfected with hepatitis B virus, with as many as 20% in southeast Asia. The exact number of patients co-infected with hepatitis B virus and hepatitis C virus is unknown; an estimated 9–30% of patients with chronic hepatitis B virus infection are co-infected with hepatitis C virus. N IB SC /S cie nc e Ph ot o Li br ar y

Depressive Symptomatology, Syndromal Depression, and HIV-Associated Neurocognitive Disorder (HAND)

The article, “Associations between depressive symptomatology of neurocognitive impairment in HIV/AIDS” by Tymchuk et al., is a scholarly work that addresses relationships and interactions between depressive symptoms and cognitive impairment in patients with HIV or AIDS. Depressive symptoms have been reported to affect up to 65% of patients with HIV in the era of effective ART, and HIV-associated neurocognitive disorder (HAND) is thought to occur at a high rate as well (approximately 50% prevalence across studies and as high as 64% in one study, excluding complaints of cognitive impairment). Hence, these disorders may be more common in some samples than cited in the article (45% and 24.5%, respectively). The relationship between these 2 entities is a question of major clinical import today. The authors state that the overarching aim of this study was to assess the prevalence and severity of depressive symptoms, as assessed by the PHQ-9 scale, in a representative cohort of HIV/AIDS patients in Canada. One of the most important issues not addressed by this article is exactly what is connoted by the presence of “depressive symptomatology.” The “depressive symptomatology” investigated here should not be equated with a diagnosis of “major depressive disorder” (MDD), per DSM-5 criteria. The authors of the paper do not do so. Depressive symptomatology could relate to the presence of other types of depressive disorders, such as bipolar disorder with a depressive episode, cyclothymic disorder, persistent depressive disorder (dysthymia), adjustment disorder with depressed mood, substance-induced depressive disorder, and medication-induced depressive disorder (such as that associated with the antiretroviral medication, efavirenz). Further, the depressive symptomatology identified here could also relate to none of the foregoing disorders but instead to “no depressive disorder”—simply an elevated depressed mood that can occur at times in anyone in the general population. Of note regarding the differentiation between “symptoms” and “disorder”, it would have been of interest to have the data on the presence of depressive disorders to relate them to another construct on the same level—another disorder (HAND)—rather than relating a type of symptom (depressive) to another disease (HAND) and another construct level (disorder). The authors report that a subset of 65 patients within the cohort of 265 had a formal psychiatric consultation verified by examining individual patients’ cumulative problem lists. Of those, 24 (a little over one-third) were found to have MDD. However, most of this subset (41 patients; 63%) had other disorders with depressive symptoms or other types of disorders, with anxiety disorders comorbid in 11 patients. Reinforcing an earlier point, the PHQ-9 is appropriately used as a case-finding or screening scale. Elevated scores indicate the need for further assessment but do not indicate a specific diagnosis. Thus, the findings of this study are not sufficiently specific to map to a diagnosis of MDD, which would be the depressive disorder of greatest interest in terms of a relationship to HIV-associated cognitive impairment. There is also a concern that the symptoms of depression may intrinsically overlap with those of HIV-associated cognitive impairment. For example, cognitive impairment (diminished ability to think or concentrate or indecisiveness) is itself a diagnostic criterion for MDD, and the PHQ-9 has an item for “trouble concentrating on things, such as reading the newspaper or watching television.” Hence, both the symptoms of depression and the diagnosis of MDD may be confounded with HIV-associated cognitive impairment

Redefining Aging in HIV Infection Using Phenotypes

Purpose of reviewThis article critically reviews the utility of “phenotypes” as behavioral descriptors in aging/HIV research that inform biological underpinnings and treatment development. We adopt a phenotypic redefinition of aging conceptualized within a broader context of HIV infection and of aging. Phenotypes are defined as dimensions of behavior, closely related to fundamental mechanisms, and, thus, may be more informative than chronological age. Primary emphasis in this review is given to comorbid aging and cognitive aging, though other phenotypes (i.e., disability, frailty, accelerated aging, successful aging) are also discussed in relation to comorbid aging and cognitive aging.Recent findingsThe main findings that emerged from this review are as follows: (1) the phenotypes, comorbid aging and cognitive aging, are distinct from each other, yet overlapping; (2) associative relationships are the rule in HIV for comorbid and cognitive aging phenotypes; and (3) HIV behavioral interventions for both comorbid aging and cognitive aging have been limited.SummaryThree paths for research progress are identified for phenotype-defined aging/HIV research (i.e., clinical and behavioral specification, biological mechanisms, intervention targets), and some important research questions are suggested within each of these research paths.