The cerebrospinal fluid biomarker profile in an HIV-infected subject with Alzheimer’s disease

Neurological complications were common features of HIV-infection before the era of effective antiretroviral treatment (ART) and more than 20% of HIV-infected patients without treatment developed HIV-associated dementia (HAD) in late disease [1]. Severe neurological complications are today rare in patients on suppressive ART [2] while milder forms of cognitive impairment are more frequently reported [3, 4]. Neurological complications have also been described in patients on ART with suppressed viral replication in plasma but detectable viral load in the CSF, so called symptomatic CSF escape [5, 6].

In HIV, a continuous immune activation of the central nervous system (CNS) is still present despite several years of otherwise effective ART [7, 8]. This chronic inflammation, together with a long lifespan of patients on ART, has raised concerns of whether HIV infection might interact with, or even potentiate, the development of other neurocognitive diseases such as AD. Older HIV-infected persons may also be more at risk of developing HAND than younger individuals [9]. In any event, age-related morbidity will be an increasing challenge in the aging HIV-infected population. The number of HIV-infected patients, who develops neurocognitive diseases, including AD, will increase with time and it will become a challenge in those cases to differentiate between AD and different forms of HAND.

The CSF biomarker profile has been extensively studied in AD and a typical pattern is increased CSF levels of total (t-tau) and hyperphosphorylated protein tau (p-tau), indicating cortical neurodegeneration and tangle pathology, and decreased levels of amyloid-β_1–42 (Aβ42), as a sign of senile plaque pathology [10]. In HAD, a slight different pattern could be found with normal p-tau, normal or increased t-tau, and normal or decreased Aβ42 [11‐16]. Other CSF markers, such as soluble amyloid precursor proteins (sAPPs) and neurofilament light protein (NFL) also have a different pattern in AD as compared to HAD, with reduced sAPP levels and increased NFL levels in HAD (these levels are typically normal in AD) [11].

The CSF biomarker profile in patients with concomitant disease has not yet been defined. Here we report CSF biomarkers in an HIV-infected patient with AD.

The patient is a woman born in 1942 who was diagnosed with HIV 1998. She was infected sometimes between 1994 and 1996. ART was initiated 1998 when her CD4-cell count was 200 cells/μL. Plasma HIV RNA has been suppressed below 50 copies/μL since 2000, with only a few minor blips. CD4⁺ T cell count has remained between 800 and 1000 cells/μL for the last 8 years. The patient has a strong heredity of AD where her mother, two aunts on her mother’s side and her grandmother had AD with an onset between 70 and 80 years of age.

The patient’s cognitive impairment started in 2005 at the age of 63 years and since 2006 she has been an outpatient at the Memory Clinic of Uppsala University Hospital. In 2006, minimal mental state examination (MMSE) showed 29 points out of 30, and in where she failed to perform the simple figure copying. A CT scan of the brain in 2006 showed no signs of abnormality. A more extensive neuropsychological examination was done in 2007 and it showed predominantly normal results except for a very low performance in spatial short time memory and spatial episodic memory corresponding to right side posterior cortical functions. The conclusion was an overall good cognitive ability but with a selected cognitive impairment in spatial abilities corresponding to the patient’s own experiences. Repeated MMSE evaluation were initially stable, but a substantial performance decrease was revealed after 2011 (October 2006: 29, April 2009: 29, October 2009: 28, November 2010: 26, November 2011: 28, December 2012: 21, and October 2014: 18). In October 2009 a PET-FDG examination was done that showed decreased glucose uptake bilaterally in the apical parts of the parietal lobes, decreased uptake in the left anterior singulum and in the basal parts of the parietal lobes and the right posterior thalamus, all findings conclusive with neurodegeneration typical for AD with a frontal involvement. ApoE testing was not accomplished.

In November 2009, the patient described her problems as a change in temper, being nearer to tears, having less tolerance for stress, problems finding her way around and problems finding words. She started medication for AD with colinesterasinhibitor donepezil 5 mg qd in addition to her other prescribed medications: venlafaxine, rosuvastatin, cetirizin and ART (lamivudine, abacavir, lopinavir and ritonavir). In 2010, donepezil was changed to galantamine 8 mg qd due to side effects. After 2011, the patient had increased memory difficulties and decreased stress tolerance. She had difficulties to cook and was unable to bake. Her problems with orientation increased even at home. Her husband described her short-term memory as substantially decreased and he had to remind her of her medication. In 2012 the AD treatment with galantamine was increased to 24 mg qd. Raltegravir was temporarily added to her ART in October 2010 for a few months but was halted when CSF HIV RNA remained suppressed.