Preclinical Amyloid-β and Axonal Degeneration Pathology in Delirium Idland A-V; Wyller TB; Stoen R; Eri LM; Frihagen F; Raeder J; Chaudhry FA; Hansson O; Zetterberg H; Blennow K; Bogdanovic N, Brækhus A, Watne LO. 1 Oslo Delirium Research Group, Department of Geriatric Medicine, University of Oslo, Oslo, Norway 2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway 3 Research Group for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway 4 Department of Anesthesiology, Oslo University Hospital, Oslo, Norway 5 Department of Urology, Oslo University Hospital, Oslo, Norway 6 Department of Orthopedic Surgery, Oslo University Hospital, Oslo, Norway 7 Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway 8 Department of Clinical Sciences, Lund University, Lund, Sweden 9 Memory Clinic, Skåne University Hospital, Lund, Sweden 10 Clinical Neurochemistry Lab, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden 11 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 12 Memory Clinic, Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway
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Preclinical Amyloid-β and Axonal Degeneration Pathology in Delirium
Administrative, technical or material support: Idland, Støen, Eri, Frihagen, Brækhus, Wyller,
Watne.
Conflicts of interest: Dr. Watne has given a lecture on delirium for Lilly. Dr. Blennow has
served on Advisory Boards for IBL International and Roche Diagnostics. Prof. Wyller has
given lectures on delirium for Pfizer, Roche, AstraZeneca and Nycomed. No other
disclosures reported.
Funding/support: The study was mainly funded by the Research Council of Norway through
the program "Improving mental health of older people through multidisciplinary efforts”
(grant no 187980/H10). Further, we have received funding from Oslo University Hospital,
The Sophies Minde Foundation, The Norwegian Association for Public Health, Civitan's
Research Foundation, South-Eastern Norway Regional Health Authority, the Medical Student
Research Program at the University of Oslo, The National Association for Public Health’s
dementia research program, the Knut and Alice Wallenberg Foundation, the Research
Council, Sweden, and the Torsten Söderberg Foundation at the Royal Swedish Academy of
Sciences
Role of Funder/Sponsor: The funding sources had no role in the design and conduct of the
study; collection, management, analysis, or interpretation of the data; preparation, review or
approval of the manuscript; and decision to submit the manuscript to publication.
Additional Contributors: Knut Engedal prof. emeritus, MD, PhD, affiliated with the
Institute of Clinical Medicine, Department of Geriatrics, University of Oslo and Norwegian
National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg,
contributed to the dementia consensus diagnoses. The study nurses Elisabeth Fragaat and
Tone Fredriksen, affiliated with Department of Geratrics, Oslo University Hospital, Oslo,
Norway, Anette Hylen Ranhoff professor, MD, PhD affiliated with the Department of
Internal Medicine, Diakonhjemmet Hospital, Oslo, Norway and the Department of Clinical
Science, Kavli Research Center for Geriatrics and Dementia, University of Bergen, Bergen,
Norway, Gry Torsæter Dahl, MD, affiliated with the Department of Anesthesiology,
Diakonhjemmet Hospital, Oslo, Norway, Arne Myklebust, MD, and Dagfinn Tore Kollerøs,
MD, affiliated with the Department of Anesthesiology, Oslo University Hospital, Oslo,
Norway, contributed to data acquisition. We also acknowledge the contributions of the
Department of Gynecology, the Department of Urology, the Department of Orthopedic
Surgery and the Department of Anesthesiology at Oslo University Hospital, the Department
of Orthopedic Surgery and the Department of Anesthesiology at Diakonhjemmet Hospital in
Oslo, Norway.
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FIGURE LEGENDS
Figure 1. CSF Ab1-42, AbX-42/X-40 ratio, T-tau and Ab1-42/T-tau ratio in non-demented
patients with and without delirium.
Footnotes: Dementia status was based upon consensus between two experienced clinicians. There were 16
patients with delirium and 49 without. P-values were calculated using Mann-Whitney U-tests.
Figure 2. Delirium occurrence according to combinations of amyloid and tau pathology.
Explanatory legends: Percent of patients who developed delirium during the hospital stay according to
grouping by positive and negative Aβ-42 and P-tau values. Subjects were classified as Aβ1-42+ (< 530 ng/L) or
Aβ1-42- (≥ 530 ng/L), and P-tau+ (≥ 60 ng/L) or P-tau- (< 60 ng/L). P-values were calculated using Chi-Square
and Fisher’s Exact Tests. a) all hip fracture patients, b) hip fracture patients without dementia c) hip fracture
patients with dementia.
eFigure1. Selection of CSF samples
Explanatory legends: Cognitively normal older individual was defined as maximum one abnormal score on
cognitive tests.
TABLES
Table 1. Baseline Characteristics.
Hip Fracture Patients (n=129) Cognitively normal older individuals
(n=121) Without Delirium (n=59)
With Delirium (n=70)
P valuea
P valueb
Age, median (range) 72 (64 to 93) 83 (60 to 94) 85 (68 to 101) .02 <.001 Male, n (%) 59 (49) 13 (22) 21 (30) .31c .001c IQCODE, median (range)e
3.00 (2.69 to 3.56) 3.19 (3.00 to 5.00)
4.53 (3.00 to 5.00)
<.001 <.001
Dementia, n (%)f 0 (0) 10 (17) 54 (77) <.001c - Nursing home, n (%) - 9 (15) 34 (49) <.001c - APACHE II, median (range)g
- 8 (5 to 14) 9 (6 to 21) .004 -
Barthel ADL, median (range)
- 19 (4 to 20) 15 (3 to 20) <.001 -
ASA scoreh
I, n (%) II, n (%) III, n (%) IV, n (%)
- 1 (2) 31 (54) 25 (44) 0 (0)
0 (0) 19 (28) 47 (69) 2 (3)
-
-
Stroke or TIA, n (%) - 9 (15) 13 (19) .62c - Diabetes mellitus, n (%)
15 (12) 8 (14) 11 (16) .73c .83c
Ischemic heart disease, n (%)
16 (13) 13 (22) 18 (26) .63c .13c
Aβ1-42, ng/L, median (range)
737 (275 to 1175) 461 (125 to 1086)
267 (125 to 713)
< .001 <.001
Aβ1-42+ (< 530 ng/L), n (%)
32 (26) 36 (61) 64 (91) <.001c <.001c
T-Tau, ng/L, median (range)
347 (114 to 826) 360 (133 to 1034)
439 (91 to 1380)
.006 .92
T-tau+ (> 350 ng/L), n (%)
59 (49) 31 (53) 48 (69) .06c .63c
P-tau, ng/L, median (range)
59 (25 to 115) 55 (18 to 118) 60 (20 to 201) .25 .35
P-tau+ (≥ 60 ng/L), n (%)
55 (46) 25 (42) 35 (50) .39c .70c
AβX-42, ng/L, median (range)i
417 (88 to 1106) 225 (25 to 1029)
123.5 (38 to 612)
<0.001 <0.001
AβX-40, ng/L, median (range)i
4873 (2220 to 10187) 3488 (779 to 8535)
2916 (1130 to 6490)
0.003 <0.001
AβX-38, ng/L, median (range)i
2054 (828 to 4994) 1548 (260 to 3867)
1120 (353 to 3732)
0.004 <0.001
AβX-42/X-40, median (range)i
0.09 (0.03 to 0.13) 0.07 (0.02 to 0.14)
0.04 (0.02 to 0.14)
<.001 .001
Aβ1-42/T-tau, median (range)
2.07 (0.44 to 4.30) 1.38 (0.15 to 5.73)
0.56 (0.09 to 2.45)
<.001 <.001
Aβ1-42/P-tau, median (range)
13.09 (3.40 to 24.72) 8.96 (1.37 to 31.60)
4.40 (0.86 to 14.71)
<.001 <.001
Abbreviations: IQCODE = Informant Questionnaire on Cognitive Decline in the Elderly. APACHE II = Acute
Physiology and Chronic Health Evaluation II. Barthel ADL = Barthel Index of Activities of Daily Living. ASA-
score = Score of The American Society of Anaesthesiologists’ classification of Physical Health. TIA = Transient
Ischemic Attack. P-values were calculated using Mann-Whitney U-test if not otherwise specified. Aβ 1-42 was
measured using INNOTEST enzyme-linked immunosorbent assays (ELISA) if not otherwise specified.
a Comparing hip fracture patients with and without delirium
b Comparing cognitively normal older individuals with hip fracture patients without delirium
c Chi-square test
d Fischer´s exact test
e Missing in two patients with hip fracture without delirium and in two cognitively normal older individuals
f Based upon consensus in an expert panel
g APACHE II score without hematocrit and blood gas values
h Missing in two patients with delirium and two patients without delirium
i AβX-42, AβX-40 and AβX-38 were measured with Aβ Triplex Assay
Table 2. CSF markers in relation to delirium and dementia status.
No dementia Without Delirium
(n=49) With Delirium
(n=16)
P value
Aβ1-42, ng/L 489 (133 to 1086) 310 (125 to 633) .006 T-Tau, ng/L 351 (132 to 808) 505 (187 to 1266) .02 P-tau, ng/L 54 (18 to 118) 72 (25 to 154) .06 AβX-42, ng/L 230 (57 to 1029) 142.5 (90 to 612) 0.085 AβX-40, ng/L 3488 (967 to 8535) 3281.5 (1598 to 6490) 0.69 AβX-38, ng/L 1548 (276 to 3867) 1434 (477 to 3732) 0.67 AβX-42/X-40 .08 (.02 to .14) .04 (.03 to .14) .004 Aβ1-42/T-tau 1.59 (.16 to 5.73) .52 (.25 to 2.45) <.001 Aβ1-42/P-tau 9.96 (1.37 to 31.60) 3.89 (1.82 to 14.71) .001 Dementia P value Without Delirium With Delirium
(n=10) (n=54) Aβ1-42, ng/L 317.5 (125 to 675) 257.5 (125 to 713) .43 T-Tau, ng/L 441 (114 to 1034) 410 (91 to 1380) .67 P-tau, ng/L 61 (19 to 109) 56 (20 to 201) .94 AβX-42, ng/L 146.5 (25 to 447) 116.5 (38 to 472) 0.24 AβX-40, ng/L 3414 (779 to 5590) 2466 (1130 to 6210) 0.20 AβX-38, ng/L 1356.0 (260 to 2241) 987 (353 to 3274) 0.24 AβX-42/X-40 .05 (0.02 to 0.08) .04 (0.02 to 0.11) .24 Aβ1-42/T-tau .96 (0.15 to 1.41) .61 (0.09 to 2.39) .17 Aβ1-42/P-tau 7.21 (1.42 to 10.68) 4.61 (0.86 to 14.34) .24 Footnotes: Values are median (range). P-values were calculated using Mann-Whitney U-test.
Table 3. Logistic regression analyzes controlling for age, gender and cognition.
Explanatory legend: Logistic regression analyzes controlling for potential confounders of the association
between delirium and biomarkers in patients without dementia
Unadjusted Adjusted by age, gender and IQCODE score OR 95 % CI OR 95 % CI
Aβ1-42, ng/L .995 .992 to .999 .993 .989 to .998
T-tau, ng/L 1.004 1.001 to 1.007 1.003 1.000 to 1.006
P-tau, ng/L 1.023 1.002 to 1.045 1.019 .987 to 1.042
AβX-42/X-40 ratio x10 .058 .005 to .615 .043 .002 to .863 Aβ1-42/T-tau ratio .18 .06 to .56 .16 .04 to .61 Aβ1-42/P-tau ratio .76 .63 to .92 .75 .60 to .93 Footnotes: The table displays the odds ratio of developing delirium per unit change in the biomarkers and ratios.
AbX-42/X-40 ratio is multiplied with 10 in order to get a more meaningful OR. Abbreviations: OR = Odds
Ratio. CI = Confidence Interval. IQCODE = Informant Questionnaire on Cognitive Decline in the Elderly.
Removal of outliers, defined as standard residuals > ± 3 or Cook´s distance > 1, did not change the odds ratios
or significance of the biomarkers considerably, and outliers were therefore kept in the model.