Hyperphosphorylated tau in CSF: A biomarker approach to evaluate premature neurological aging in HIV-1?

Jan J. Krut1, Richard W. Price2, Henrik Zetterberg3, Lars Hagberg1, Paola Cinque4, Staffan Nilsson5 and Magnus Gisslén1
Affiliates: 1Institute of Biomedicine, Department of Infectious Diseases, University of Gothenburg, Sweden 2Department of Neurology, University of California San Francisco, San Francisco, CA, USA 3Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Sweden, and UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom 4Clinic of Infectious Diseases, San Raffaele Hospital, Milan, Italy 5Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden

In the combined antiretroviral treatment (cART) era, HIV-1 associated dementia (HAD) is rarely noticed. However, more discrete forms of HIV-associated neurocognitive disorders are still common, even in patients on cART. Hyperphosphorylated tau in CSF (p-tau) is a biomarker reflecting pathological phosphorylation of tau protein and is used clinically in diagnosis of Alzheimer disease. It is not influenced by neuroinflammation, and increases slowly in normal aging. In this study we decided to assess if p-tau can be used as a marker of premature neurological aging in HIV patients.

With a cross-sectional retrospective design, P-tau (phosphorylated at threonine 181) concentrations in CSF were measured with an enzyme-linked immunoassay in four populations; HIV-1 infected neuroasymptomatic (NA) patients without treatment (n=172), HIV-infected patients on cART and plasma HIV-RNA <50 copies/ml (n=68), HAD (n=33) and HIV-negative controls (n=291). For statistical measures, correlations and linear regression were used.

P-tau and age showed significant positive correlations in the cART group and HIV-negative controls (p<0.01 and p<0.001 respectively), whereas no significant correlations were found in the NA and HAD groups. When looking at the HIV-positive population as a whole, a significant difference was seen in slope compared to controls (p<0.001).

HIV-infected on cART and HIV-negative controls show significant positive correlations of p-tau with age. No such connection could be found in untreated HIV. Patients with HAD do not have higher p-tau levels than asymptomatic subjects. Several younger untreated HIV-infected individuals, both asymptomatic and with HAD, had high p-tau while this is not the case in older individuals. The mechanism behind this skewness remains to be explained.