The stages of disease progression in terms of cognitive functioning are typically classified into three groups, using the system developed by the American Academy of Neurology¹: (a) neuropsychological deficit (below-expected performance in one domain) or neuropsychological impairment (impairment in two or more cognitive domains), (b) minor cognitive motor disorder (MCMD; neuropsychological impairment with mild functional impairment) (Table 12.1), and (c) HIV-associated dementia (HAD; involves marked cognitive and functional impairment sufficient to interfere with daily life, of at least 1 month’s duration) (Table 12.2). Although these terms are widely used throughout the literature, there is as yet no consensus as to the best system of measurement.

A meta-analysis of 41 primary studies of neuropsychological test performance (8,616 total participants) revealed that overall, disease progression was accompanied by increasingly larger effect sizes between control (seronegative), asymptomatic, symptomatic, and patients with

AIDS, respectively.² Differences between the asymptomatic and control (seronegative) groups were present, but small (0.2 standard deviations), whereas larger effect sizes were noted between both the symptomatic groups and groups with AIDS compared to control subjects. In later stages of the disease, motor deficits were most prominent, with deficits also present in problem-solving and other executive functions, rate of information processing, expressive language, memory, and, to a lesser degree, attention and concentration. The progression of cognitive decline followed a frontal-subcortical pattern initially, with the areas of greatest deficit early in the disease (motor and executive functions) being those subserved by these brain regions and neural circuits. In later stages of the disease, abilities such as memory and visuospatial skills, which are less dependent on frontal-subcortical circuitry, also declined. Notably, there was a high degree of variability among the studies included in this quantitative review. One factor suggested by the authors relates to test specificity; to the extent that some instruments measure more than one discrete domain of cognitive functioning, results of analyses using these instruments varied. Another issue is the method of categorization of individuals by disease stages and failure to consistently account for the wide range of psychosocial variables that may affect test performance, such as demographic characteristics including age and education, the presence of affective disorders, and differences in medical comorbidity and substance use history.

Results of an 8-year longitudinal study in which participants underwent neuropsychological evaluation at 6-month intervals were largely consistent with the above meta-analysis, also revealing a decline in cognitive function with HIV disease progression.³ Of the five functional domains assessed (fine motor speed, attention, verbal memory, executive functioning, and information processing speed), fine motor speed and information processing speed showed the most significant decline over time, and this decline became increasingly prominent as individuals developed AIDS-defining illnesses.

Persons with HIV-related cognitive impairment typically show fluctuation in cognitive signs and symptoms. There can be stable deficits without progression. Some individuals will experience only episodic worsening that may or may not be associated with somatic changes associated with active systemic disease. Other individuals will experience more rapid progression associated with advanced central nervous system (CNS) disease. The group with rapid progression and deterioration of CNS function also has more advanced symptomatic HIV disease and fully developed AIDS. No matter which group, cognitive impairment is not a benign condition. Psychosocial dysfunction, diminished quality of life, poor treatment compliance, and decreased survival are associated with all types of cognitive impairment.⁴ Although progression of cognitive impairment is typically idiosyncratic, some reports suggest that it can be predicted by HIV ribonucleic acid (RNA) in the cerebrospinal fluid (CSF).⁵

The 2002 meta-analysis by Reger et al.² includes a list of all the neuropsychological tests employed in the 41 studies cited.² These are categorized by cognitive domain and show the percentage of primary studies in which each measure was used. To a large degree, these overlap with the National Institute of Mental Health’s core neuropsychological battery employed in the assessment of patients with HIV-1⁶ (Table 12.3).

In addition to the cognitive domains of attention/concentration, executive functioning (including abstraction and problem solving), information-processing speed, language/verbal abilities, visuospatial/visuoconstruction skills, and both visual and verbal memory, many studies also include measures of overall intellectual abilities, motor skills, and psychiatric symptoms, particularly those related to anxiety and affective disorders.

Differences between asymptomatic and symptomatic groups have been more frequently observed when comprehensive test batteries were administered compared to briefer batteries or screening instruments.⁷ Clinical ratings have also been shown to be of value in assessing the presence and degree of neuropsychological impairment.⁸ In contrast to data analysis with an emphasis on mean differences between groups, clinical ratings provide a closer picture of
individual profile differences across domains. This is particularly effective for the study of individuals with HIV infection, who, at least early in the disease course, show relatively mild and diverse types of neuropsychological deficits. Using the process advocated in some studies, clinical ratings are made by grouping scores from tests according to the cognitive domain measured, and then rating each domain on a scale of 1 (above average) to 9 (severe impairment).⁹ This method showed very strong inter-rater reliability on ratings of severity of impairment across domains, but was less effective in making neurocognitive diagnoses, possibly because of issues related to comorbidity and other risk factors.⁸ Used as a method of summarizing neuropsychological test results, global deficit scores have been shown to have strong positive predictive value for neuropsychological impairment. A cut point of 0.50 or greater was determined to produce maximum sensitivity and specificity for classification of impairment.¹⁰