Since 1998, the National NeuroHIV Tissue Consortium (NNTC) has maintained a biorepository of well-characterized systemic, central nervous system (CNS) and peripheral nervous system (PNS) tissue, samples from other organs, and fluid specimens (e.g., blood, cerebrospinal fluid [CSF]) that are complemented by annotated clinical data. NNTC specimens and data are obtained from persons with HIV (PWH) and persons without HIV (PWoH) and are made available to all qualified requestors; these include longitudinal neuromedical and neuropsychological evaluations, neuroimaging, synchronous specimen collections, and post-mortem specimens collected by autopsy. The breadth of NNTC study assessments and their intensity of sampling provide information relevant to understanding the pathogenesis of HIV-associated neurological and neurobehavioral dysfunction. As the landscape of HIV has evolved over time, NNTC protocols have similarly adapted to keep apace with the changing nature of the pandemic, HIV treatment, and research priorities. For example, the current NNTC protocol emphasizes capturing contemporary issues relevant to aging cohorts with multiple medical comorbidities, understanding the interplay between HIV and substance use, and measuring psychological phenomena from a Research Domain Criteria (RDoC) approach [1]. 

NNTC participants in the active cohort are followed longitudinally and are assigned to one of two frequencies of follow-up, or study visit tiers, based on their clinical disease severity and degree of social stability. Individuals who are characterized by a high degree of medical or social instability are in Tier 1 and are scheduled annually to maintain contact and capture change in status. Individuals deemed to be at average or low risk for loss to follow-up or death are in Tier 2 and scheduled for comprehensive assessments once every two years.  An overview, summarizing the current complement of assessments that compose the NNTC battery, and a schedule of assessments (SOA) detailing their timing of administration, is provided below.

Overview of NNTC’s Domains of Assessment

Neuromedical Domain

The NNTC neuromedical evaluation consists of physical assessments, interviews, self-report questionnaires, and tests performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. The main aims of the neuromedical evaluation are to:

  • Diagnose neurological disorders, using a general neurologic examination focused on prevalent conditions among PWH (e.g., peripheral neuropathy, cerebrovascular disease, and motor dysfunction).
  • Conduct blood a CSF collection for the characterization of HIV disease (e.g., HIV viral loads, CD4 counts) as well as other routine clinical labs.
  • Describe antiretroviral therapy use and immunologic status.
  • Elaborate on major medical disorders and co-morbid conditions that may cause or influence HIV-associated neurological and neurobehavioral abnormalities, with a focus on metabolic disorders (i.e., hypertension, diabetes, hyperlipidemia, obesity) and hepatitis/liver disease.
  • Collect data to enable quantitative risk assessments for cardiovascular and cerebrovascular disease and frailty, which are all relevant to aging PWH.

Neurobehavioral Domain

The NNTC neurobehavioral evaluation consists of performance-based measures of cognition, self-report measures of psychosocial functioning, and structured diagnostic interviews to identify substance use and psychiatric disorders. The main aims of the neurobehavioral evaluation are to:

  • Assess neuropsychological functioning and provide characterization of global and domain-specific functioning (e.g., learning, speed of information processing) and impairment such that diagnostic criteria (e.g., HIV-associated Neurocognitive Disorders) can be applied.
  • Characterize the psychiatric and substance use functioning of participants.
  • Evaluate the major domains of human functioning, as identified by the RDoC: Negative Valence, Positive Valence, Cognitive Systems, Social Processing, Arousal Regulatory, and Sensorimotor Functioning.
  • Provide characterization relevant to neurobehavioral phenotypes and biotypes that are amenable to treatments and clinical interventions.

Neuroimaging Domain

The NNTC neuroimaging protocol is a multimodal assessment of brain structure, functional connectivity, and metabolic processes using modalities recommended for investigating CNS Complications among PWH, including structural MRI with T1-weighted, T2-weighted, and FLAIR sequences, single voxel MR spectroscopy, and multiband resting state fMRI [2]. The primary aims of the neuroimaging protocol are to:

  • Identify focal pathologies that may contribute to cognitive and neurological abnormality in the context of HIV, neurodegenerative disorders, and brain aging
  • Investigate variability among persons aging on ART, who may be heterogeneous with regards to states of neuroinflammation, neurodegeneration, and structural change.
  • Obtain longitudinal data to measure differences over time, with elaboration of phenotypes that are related to regional neurodegenerative phenomena, generalized neuroinflammatory processes, and deficits in connectivity.
  • Explore functional connectivity within the neural networks that are implicated by RDoC constructs (e.g., Cognitive Systems, Negative Affect, and Positive Affect).

References

  1. Insel TR. The NIMH research domain criteria (RDoC) project: precision medicine for psychiatry. Am J Psychiatry. 2014;171(4):395-397.

  2. O’Connor EE, Sullivan EV, Chang L, et al. Imaging of brain structural and functional effects in people with human immunodeficiency virus. J Infect Dis. 2023;227(Supplement_1):S16-S29.