Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer's disease

doi:10.1186/s13195-018-0426-3

Multicenter Study

. 2018 Sep 25;10(1):98.

doi: 10.1186/s13195-018-0426-3.

Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer's disease

Umesh Gangishetti¹, J Christina Howell^{1

2}, Richard J Perrin^{3

4}, Natalia Louneva⁴, Kelly D Watts¹, Alexander Kollhoff¹, Murray Grossman^{5

6

7}, David A Wolk^{8

7}, Leslie M Shaw⁹, John C Morris^{3

10}, John Q Trojanowski^{8

5

9}, Anne M Fagan^{3

10}, Steven E Arnold^{8

5

11}, William T Hu^{12

13}

Affiliations

¹ Department of Neurology, Emory University, 615 Michael Street, 505F, Atlanta, GA, 30322, USA.
² Department of Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA.
³ Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA.
⁴ Department of Pathology, Washington University, St. Louis, MO, USA.
⁵ Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Penn FTD Center, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Penn Memory Center, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Neurology, Washington University, St. Louis, MO, USA.
¹¹ Present Address: Massachusetts General Hospital, Boston, MA, USA.
¹² Department of Neurology, Emory University, 615 Michael Street, 505F, Atlanta, GA, 30322, USA. william.hu@emory.edu.
¹³ Department of Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA. william.hu@emory.edu.

PMID: 30253800
PMCID: PMC6156847
DOI: 10.1186/s13195-018-0426-3

Multicenter Study

Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer's disease

Umesh Gangishetti et al. Alzheimers Res Ther. 2018.

. 2018 Sep 25;10(1):98.

doi: 10.1186/s13195-018-0426-3.

Authors

Affiliations

¹ Department of Neurology, Emory University, 615 Michael Street, 505F, Atlanta, GA, 30322, USA.
² Department of Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA.
³ Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA.
⁴ Department of Pathology, Washington University, St. Louis, MO, USA.
⁵ Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Penn FTD Center, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Penn Memory Center, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Neurology, Washington University, St. Louis, MO, USA.
¹¹ Present Address: Massachusetts General Hospital, Boston, MA, USA.
¹² Department of Neurology, Emory University, 615 Michael Street, 505F, Atlanta, GA, 30322, USA. william.hu@emory.edu.
¹³ Department of Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA. william.hu@emory.edu.

PMID: 30253800
PMCID: PMC6156847
DOI: 10.1186/s13195-018-0426-3

Abstract

Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aβ), tau, neuronal loss, and other associated biological events. While levels of cerebrospinal fluid (CSF) Aβ and tau peptides have enhanced the antemortem detection of AD-specific changes, these two markers poorly reflect the severity of cognitive and functional deficits in people with altered Aβ and tau levels. While multiple previous studies identified non-Aβ, non-tau proteins as candidate neurodegenerative markers to inform the A/T/N biomarker scheme of AD, few have advanced beyond association with clinical AD diagnosis. Here we analyzed nine promising neurodegenerative markers in a three-centered cohort using independent assays to identify candidates most likely to complement Aβ and tau in the A/T/N framework.

Methods: CSF samples from 125 subjects recruited at the three centers were exchanged such that each of the nine previously identified biomarkers can be measured at one of the three centers. Subjects were classified according to cognitive status and CSF AD biomarker profiles as having normal cognition and normal CSF (n = 31), normal cognition and CSF consistent with AD (n = 13), mild cognitive impairment and normal CSF (n = 13), mild cognitive impairment with CSF consistent with AD (n = 23), AD dementia (n = 32; CSF consistent with AD), and other non-AD dementia (n = 13; CSF not consistent with AD).

Results: Three biomarkers were identified to differ among the AD stages, including neurofilament light chain (NfL; p < 0.001), fatty acid binding protein 3 (Fabp3; p < 0.001), and interleukin (IL)-10 (p = 0.033). Increased NfL levels were most strongly associated with the dementia stage of AD, but increased Fabp3 levels were more sensitive to milder AD stages and correlated with both CSF tau markers. IL-10 levels did not correlate with tau biomarkers, but were associated with rates of longitudinal cognitive decline in mild cognitive impairment due to AD (p = 0.006). Prefreezing centrifugation did not influence measured CSF biomarker levels.

Conclusion: CSF proteins associated with AD clinical stages and progression can complement Aβ and tau markers to inform neurodegeneration. A validated panel inclusive of multiple biomarker features (etiology, stage, progression) can improve AD phenotyping along the A/T/N framework.

Keywords: Biomarkers; Fatty acid binding protein; Interleukin-10; Mild cognitive impairment; Neurofilament light chain.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by Institutional Review Boards at Emory University, University of Pennsylvania, and Washington University. All participants previously consented to CSF storage and analysis of stored CSF samples.

Consent for publication

Not applicable.

Competing interests

LMS has received personal compensation for activities with Roche Diagnostics which produces CSF amyloid and tau assays. AMF is on the Scientific Advisory Boards for Roche Diagnostics which produces CSF amyloid and tau assays. WTH consults for ViveBio, LLC., which manufactures lumbar puncture trays; has a patent (assignee: Emory University) on the use of CSF p/t-Tau ratio in the evaluation of FTLD; has received research support from Fujirebio USA and Avid Pharmaceuticals; has received travel support from Hoffman La Roche and Abbvie. The remaining authors declare that they have no competing interests,

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
CSF analyte levels (Z scores) for the combined cohort of normal cognition without CSF biomarkers consistent with Alzheimer’s disease (NC^–) and Alzheimer’s disease (AD) dementia subjects. To account for inter-center variability, a center-specific Z score was calculated for each analyte by grouping NC^– and AD dementia subjects together to calculate the group mean and standard deviation. Student’s t tests were then used to compare the Z scores of NC^– and AD dementia subjects across the three centers, with FDR < 5%. Bars represent median and interquartile ranges, and the unadjusted p values are shown. Fabp3 fatty acid binding protein 3, IL interleukin, MCP-1 monocyte chemotactic protein 1, NfL neurofilament light chain, TNF tumor necrosis factor, YKL40 chitinase-3-like protein 1

**Fig. 2**
CSF levels (Z scores) of neurofilament light chain (NfL) (a), fatty acid binding protein 3 (Fabp3) (b), and interleukin (IL)-10 (c) in subjects with normal cognition (NC), mild cognitive impairment (MCI), Alzheimer’s disease (AD) dementia, and other non-AD dementia (OD). (*p < 0.001; ^†p < 0.005; p < 0.05 for other comparisons indicated). Differences between different subgroups are summarized in d, with direction of change reflecting the stage with more severe pathology or cognitive impairment

**Fig. 3**
Correlations between CSF tau-related proteins and neurofilament light chain (NfL) and fatty acid binding protein 3 (Fabp3) levels. Fabp3 levels correlated strongly with total tau (t-Tau) and phosphorylated tau (p-Tau₁₈₁) levels, while NfL levels correlated better with t-Tau than p-Tau₁₈₁ levels. AD Alzheimer’s disease, MCI mild cognitive impairment, NC normal cognition

**Fig. 4**
Relationship between CSF interleukin (IL)-10 levels, rates of cognitive decline, and preanalytical processing. Lower CSF IL-10 levels were associated with greater decline in memory functions (adjusting for age, gender, race, education) in MCI⁺. a Memory Z scores were derived from averaging verbal and visual delayed recall Z scores. Mixed linear modeling was performed using IL-10 as a continuous variable (p = 0.005), and IL-10 levels are shown as tertiles for illustrative purposes (open triangle, open circle, and filled triangle represent top, middle, and bottom quartiles). b Centrifugation of CSF after collection but before freezing did not alter IL-10 levels or levels of two other biomarkers (neurofilament light chain (NfL) and IL-7)

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References

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[1] Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Jr, Kaye J, Montine TJ, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:280–292. doi: 10.1016/j.jalz.2011.03.003. - DOI - PMC - PubMed

[2] Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Jr, Kaye J, Montine TJ, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:280–292. doi: 10.1016/j.jalz.2011.03.003. - DOI - PMC - PubMed

[3] Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:270–279. doi: 10.1016/j.jalz.2011.03.008. - DOI - PMC - PubMed

[4] Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:270–279. doi: 10.1016/j.jalz.2011.03.008. - DOI - PMC - PubMed

[5] McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol. 2001;58:1803–1809. doi: 10.1001/archneur.58.11.1803. - DOI - PubMed

[6] McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol. 2001;58:1803–1809. doi: 10.1001/archneur.58.11.1803. - DOI - PubMed

[7] Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012;8:1–13. doi: 10.1016/j.jalz.2011.10.007. - DOI - PMC - PubMed

[8] Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012;8:1–13. doi: 10.1016/j.jalz.2011.10.007. - DOI - PMC - PubMed

[9] Jack CR, Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, et al. NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14:535–562. doi: 10.1016/j.jalz.2018.02.018. - DOI - PMC - PubMed

[10] Jack CR, Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, et al. NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14:535–562. doi: 10.1016/j.jalz.2018.02.018. - DOI - PMC - PubMed

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Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer's disease

Affiliations

Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer's disease

Authors

Affiliations

Abstract

Conflict of interest statement

Ethics approval and consent to participate

Consent for publication

Competing interests

Publisher’s Note

Figures

Similar articles

Cited by

References

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