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Amyloid and tau cerebrospinal fluid biomarkers in HIV infection.

Gisslén M, Krut J, Andreasson U, Blennow K, Cinque P, Brew BJ, Spudich S, Hagberg L, Rosengren L, Price RW, Zetterberg H - BMC Neurol (2009)

Bottom Line: CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups.CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups.Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Infectious Diseases, University of Gothenburg, Sahlgrenska University Hospital, SE-416 85 Gothenburg, Sweden. magnus.gisslen@infect.gu.se

ABSTRACT

Background: Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients.

Methods: In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPalpha and sAPPbeta), amyloid beta fragment 1-42 (Abeta1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease.

Results: CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Abeta1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections.

Conclusions: Parallel reductions of CSF sAPPalpha and sAPPbeta in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.

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Selected marker correlations across patient groups. The four panels show relationships between markers: Panel A between sAPPα and sAPPβ, Panel B between Aβ1-42 and sAPPβ, Panel C between Aβ1-42 and sAPPα, and Panel D between p-tau and t-tau. Symbols for all four panels are defined in Panel A. The diagonal lines show linear regressions with 95% confidence intervals; each panel lists the P value and r2 for the regression. Abbreviations are those given in Figure 1.
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Figure 3: Selected marker correlations across patient groups. The four panels show relationships between markers: Panel A between sAPPα and sAPPβ, Panel B between Aβ1-42 and sAPPβ, Panel C between Aβ1-42 and sAPPα, and Panel D between p-tau and t-tau. Symbols for all four panels are defined in Panel A. The diagonal lines show linear regressions with 95% confidence intervals; each panel lists the P value and r2 for the regression. Abbreviations are those given in Figure 1.

Mentions: We also examined the correlations among the different biomarkers across the subject groups, with particular attention to the relationships within the amyloid pathway and between the tau forms. Initial exploration showed significant nonparametric correlations between the markers in the same pathways (sAPPα vs sAPPβ, P < 0.0001, rs = 0.957; sAPPα vs Aβ1-42 P = 0.06, rs = 0.153; sAPPß vs Aβ1-42 P < 0.05, rs = 0.195; t-tau vs p-tau P < 0.0001, rs = 0.462); sAPPα and sAPPβ also correlated with t-tau, P < 0.0001, rs = -0.644 and -0.736, and with p-tau P < 0.01 and P < 0.05, rs = 0.170 and 0.237. Figure 3A shows the high correlation of sAPPα and sAPPβ across the entire sample, indicating that the concentrations of these two metabolites were similarly altered by the different pathologies of the subjects. While Aβ1-42 also correlated with sAPPs across their range, the relationship was much looser. Figure 3B shows the variability within each clinical group in the CSF Aβ1-42 in relation to their CSF sAPPβ levels; this is perhaps most notable at low (abnormal) sAPPβ concentrations where the wide range of Aβ1-42 values was contributed by the ADC and opportunistic infection patients. Results were similar when Aβ1-42 was compared to sAPPα (Figure 3C). In Figure 3D showing the relationship of p-tau to t-tau concentrations, the different diagnoses influenced the regression in one or another direction - the elevated p-tau in the Alzheimer's disease patients with high t-tau pulled the right end of the line up, while the low p-tau in the ADC and infection patients with elevated t-tau pulled it in the opposite direction.


Amyloid and tau cerebrospinal fluid biomarkers in HIV infection.

Gisslén M, Krut J, Andreasson U, Blennow K, Cinque P, Brew BJ, Spudich S, Hagberg L, Rosengren L, Price RW, Zetterberg H - BMC Neurol (2009)

Selected marker correlations across patient groups. The four panels show relationships between markers: Panel A between sAPPα and sAPPβ, Panel B between Aβ1-42 and sAPPβ, Panel C between Aβ1-42 and sAPPα, and Panel D between p-tau and t-tau. Symbols for all four panels are defined in Panel A. The diagonal lines show linear regressions with 95% confidence intervals; each panel lists the P value and r2 for the regression. Abbreviations are those given in Figure 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2807422&req=5

Figure 3: Selected marker correlations across patient groups. The four panels show relationships between markers: Panel A between sAPPα and sAPPβ, Panel B between Aβ1-42 and sAPPβ, Panel C between Aβ1-42 and sAPPα, and Panel D between p-tau and t-tau. Symbols for all four panels are defined in Panel A. The diagonal lines show linear regressions with 95% confidence intervals; each panel lists the P value and r2 for the regression. Abbreviations are those given in Figure 1.
Mentions: We also examined the correlations among the different biomarkers across the subject groups, with particular attention to the relationships within the amyloid pathway and between the tau forms. Initial exploration showed significant nonparametric correlations between the markers in the same pathways (sAPPα vs sAPPβ, P < 0.0001, rs = 0.957; sAPPα vs Aβ1-42 P = 0.06, rs = 0.153; sAPPß vs Aβ1-42 P < 0.05, rs = 0.195; t-tau vs p-tau P < 0.0001, rs = 0.462); sAPPα and sAPPβ also correlated with t-tau, P < 0.0001, rs = -0.644 and -0.736, and with p-tau P < 0.01 and P < 0.05, rs = 0.170 and 0.237. Figure 3A shows the high correlation of sAPPα and sAPPβ across the entire sample, indicating that the concentrations of these two metabolites were similarly altered by the different pathologies of the subjects. While Aβ1-42 also correlated with sAPPs across their range, the relationship was much looser. Figure 3B shows the variability within each clinical group in the CSF Aβ1-42 in relation to their CSF sAPPβ levels; this is perhaps most notable at low (abnormal) sAPPβ concentrations where the wide range of Aβ1-42 values was contributed by the ADC and opportunistic infection patients. Results were similar when Aβ1-42 was compared to sAPPα (Figure 3C). In Figure 3D showing the relationship of p-tau to t-tau concentrations, the different diagnoses influenced the regression in one or another direction - the elevated p-tau in the Alzheimer's disease patients with high t-tau pulled the right end of the line up, while the low p-tau in the ADC and infection patients with elevated t-tau pulled it in the opposite direction.

Bottom Line: CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups.CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups.Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Infectious Diseases, University of Gothenburg, Sahlgrenska University Hospital, SE-416 85 Gothenburg, Sweden. magnus.gisslen@infect.gu.se

ABSTRACT

Background: Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients.

Methods: In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPalpha and sAPPbeta), amyloid beta fragment 1-42 (Abeta1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease.

Results: CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Abeta1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections.

Conclusions: Parallel reductions of CSF sAPPalpha and sAPPbeta in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.

Show MeSH
Related in: MedlinePlus