Refining the neuropsychological battery

At the Center's inception in 1989 we deployed a comprehensive neuropsychological ensemble since, at that time, we lacked systematic information on qualitative and quantitative features of HIV-associated neurocognitive impairment at different stages of disease. Hence, it was necessary to assemble a battery that had broad coverage, as well as sufficient sensitivity to detect what might be subtle, early changes. The early experience of the HNRC allowed us to make substantive contributions to the NIMH Consensus Conference that resulted in the publication of the NIMH recommended neuropsychological battery (Butters et al., 1990). As our experience deepened, we were able to make successive changes in the neuropsychological battery in order to streamline it and make it more specific, as well as to propose "step downs" for use in more infirm advanced patients. The statistical and clinical decision rules that led to NP battery revision were reported in Grant et al. (1997). The neuropsychological experience of the HNRC again contributed significantly to position statements both by the NIH and the WHO in regard to research on neurocognitive complications of HIV (Bloom & Rausch, 1997; UNAIDS, 1998). In 1999 the HNRC further revised the battery, and included neuropsychological test measures that were the most sensitive to HIV-related impairments, had comprehensive, demographically-corrected norms, and in many instances had alternate forms available for increased sensitivity across multiple visits (Woods et al., 2004).

The HNRC continues to actively support studies to develop novel approaches to detecting HIV-associated NP impairment. Current directions of interest include utilization of paradigms derived from cognitive neuropsychology to elucidate the component processes of cognitive deficits in HIV, which may improve the detection and differential diagnosis of HIV-associated neurocognitive disorders.

Norms appropriate to special populations

The changing demographics of the HIV epidemic meant that increasing numbers of under-represented minorities including African Americans and Hispanics were at increased risk for HIV infection. Although investigators who are part of the HNRC had been at the forefront for developing norms for the non-Hispanic White population (e.g., Heaton et al., 1991; Heaton et al., 1992), it became evident that the use of such norms overstated the likely rate of neurocognitive impairment in minority groups. Accordingly, Miller and colleagues at the HNRC conducted a normative study of African Americans (Miller et al., 1998), the results of which contributed to a comprehensive manual of demographically corrected norms (Heaton et al., 2004). By applying correct norms, we demonstrated that the apparently higher rate of NP impairment in African Americans was not real (Miller et al., 1997).

Similarly, Heaton and colleagues are now in the process of completing norms for Spanish-speaking Hispanics.

As increased emphasis is placed on understanding the course of HIV neurocognitive impairment in international environments, the HNRC has become involved in NP methods development for use in resource-limited settings. Preliminary results from a pilot study in China using a translated HNRC battery suggest that the selected NP battery can be adapted for use in international populations across a broad range of educational levels, and this work has resulted in a funded R01 application. Similar adaptations are underway for use in studies in Brazil and India.

Operationalizing the diagnosis of HIV-associated neurocognitive disorders

HNRC investigators recognized that terms such as "HIV dementia" were unacceptably broad leading to underestimates and overestimates of HIV-associated neurocognitive complications (Grant & Martin, 1994). Accordingly, our group proposed and conducted testing on research criteria for three levels of neurocognitive complications: (a) asymptomatic (subsyndromic) neuropsychological impairment; (b) mild neurocognitive disorder (similar to the AAN notion of minor cognitive motor disorder or MCMD); and (c) HIV-associated dementia. The latter two have been termed syndromal impairment. The value of this approach was recognized by the NIH Consensus Conference (Bloom & Rausch, 1997) and was subsequently adopted by the National NeuroAIDS Tissue Consortium, a group of four NIH-funded neuroAIDS tissue banks.

Data from HNRC studies and other investigations suggests that in the era of HAART there may be a number of possible patterns of neurocognitive impairment. At the recent NIH work group “A Critical Re-Examination of Adequacy and Utility of AAN 1991 Definitional Criteria” (NIMH/NINDS: Frascati, Italy, 6/13/05), HNRC investigators contributed to a new consensus that allows for at least the following patterns of impairment: (a) a mild form of neurocognitive disorder that reverses with ARV treatment either permanently, or at least for a very long time; (b) a relapsing-remitting form akin to demyelinating disorders wherein persons may have mild impairment at initial presentation, then normalize, and subsequently again become impaired; (c) a long-term static impairment of variable severity, generally mild; (d) a sub-group of individuals who manifest steady, slow deterioration, or deterioration after a period of stability; and (e) a small number of cases who manifest rapid, catastrophic decline, generally after ARV treatment options have been exhausted or, occasionally, via an immune reconstitution linked pathogenesis.

Reliable measurement of neurocognitive change

The ability to be confident that changes in neurocognitive performance truly reflect some biological change and not simply practice effect or measurement error is central to many aspects of neuroAIDS research, particularly studies on treatment efficacy. Working with our Statistics group, HNRC neuropsychologists are in the process of establishing standards for inferring "real" change that may then be published as "change norms" for various demographic groups.

A recent HNRC study applied a modified Reliable Change Index (RCI) methodology across a focused battery of commonly used NP tests to generate an indicator of overall cognitive stability (Woods et al., 2006). Findings from this study may be useful for both clinicians and researchers seeking normative standards for determining reliable changes in performance across comparable batteries employed by several national, multisite studies (e.g, National NeuroAIDS Tissue Consortium). Such data will also be useful for clinical trials and single, within-groups studies when placebo-controlled studies are difficult to implement.

Instruments for documenting "real life" implications of HIV neurocognitive impairment

Reliably measuring the "meaning" of neurocognitive findings is just as important as reliably documenting the findings themselves. Neuropsychological data in the absence of functional implications are of limited interest. Therefore, the HNRC group has been developing and refining methodologies for the objective measurement of vocational skills, medication management, driving skills, and other types of abilities that are critical for day-to-day functioning. Examples of these efforts are reported in Heaton et al. (1996, 2004) and Marcotte et al. (1999, 2004), and Rivera-Mindt et al. (2001).

Innovations in brain imaging

It was understood early that structural brain changes, as appreciated by routine MRI of the brain, were detected only in advanced stages of disease. At the same time, neuropsychological data strongly indicated earlier brain involvement. Accordingly, HNRC investigators led by Dr. Terry Jernigan developed improved techniques for quantitating various gray and white matter regions as well as CSF volumes in the brain to add sensitivity to our in vivo morphometry. As a result, we were able to detect regional changes in brain structure even in non-demented persons with AIDS (Jernigan et al., 1993). Equally important, the Neuroimaging group worked with the Statistical group to develop improved techniques for repeated measures analysis of morphometric information. As a result, we were able to detect progressive reductions in selected gray, white, and subcortical volumes in relation to progression of disease, including progressive changes during the medically asymptomatic phase (Stout et al., 1998). More recently, we have utilized MR spectroscopy to examine the CNS impact of antiretroviral treatment (Schweinsburg et al., 2005) and co-factors, such as methamphetamine use (Taylor et al., 2000).

Improved statistical approaches

Neurobehavioral research on HIV poses many challenges related to multiple comparisons, longitudinal analyses, non-linear associations, and so forth. The HNRC statistics unit has continued in efforts to make innovations that both specifically address our research needs, and may be generalizable to other similar problems. Examples include refinement of the "p-plot" approach to balancing between types I and II error (Abramson et al., 1999), and growth curve approaches to measuring change over time (Abramson et al., 2002). Other innovative techniques extended and/or custom-programmed at the HNRC include an algorithm for computing power and sample size for any selected components of a multivariate linear model, bootstrap variations on parametric tests (offering higher asymptotic accuracy), and the empirical Bayes modeling of count data (e.g. accident-“proneness”).

Novel methods for analyzing neurodegeneration and measuring neuronal populations, proteins and select receptors

HNRC investigators have developed innovative methods to further analyze the neurodegenerative alteration in the CNS of AIDS patients by developing sensitive techniques to quantitatively analyze dendritic and synaptic complexity as well as selective neuronal populations (Masliah et al., 1997). These studies have incorporated the use of the confocal laser scanning microscope, the image analyzer Quantimet 570C and highly sensitive and reproducible immunocytochemical assays with vibratome sections. Also, our group developed stereological techniques in combination with the confocal methods for analysis of synaptic and neuronal density (Everall et al., 1999). We also developed dot-blot assays for quantification of synaptophysin and other synaptic proteins (Masliah et al. 1998), as well as molecular assays for quantitative analysis of cytokines and chemokine receptors using ribonuclease protection assays. Finally, HNRC investigators have developed novel transgenic animal models of HIVE by using animals over-expressing gp120, Nef and Tat among others.