T Brendt

Annals of Medicine
2024, VOL. 56, NO. 1, 2304650

https://doi.org/10.1080/07853890.2024.2304650
Research Article
Brain-Derived neurotrophic factor and inflammatory biomarkers are

unaffected by acute and chronic intermittent hypoxic-hyperoxic exposure
in geriatric patients: a randomized controlled trial
Tom Behrendta# , Jessica Ibanez Quisilimaa#, Robert Bielitzkia , Martin Behrensb ,
Oleg S. Glazachevc , Tanja Brigadskid , Volkmar Leßmanne,f and Lutz Schegaa
a
Department of Sport Science, Chair for Health and Physical Activity, Otto-von-Guericke University Magdeburg, Magdeburg, Germany;
b
University of Applied Sciences for Sport and Management Potsdam, Potsdam, Germany; cDepartment of Human Physiology, Institute
of Clinical Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; dDepartment of Informatics and Microsystem
Technology, University of Applied Sciences Kaiserslautern, Zweibrücken, Germany; eInstitute of Physiology, Otto-von-Guericke University
Magdeburg, Medical Faculty, Magdeburg, Germany; fCenter for Behavioral Brain Sciences, Magdeburg, Germany
ABSTRACT ARTICLE HISTORY

Background: Animal and human studies have shown that exposure to hypoxia can increase Received 11 July 2023
brain-derived neurotrophic factor (BDNF) protein transcription and reduce systematic inflammatory Revised 20 November
cytokine response. Therefore, the aim of this study was to investigate the acute and chronic 2023
Accepted 24 November
effects of intermittent hypoxic-hyperoxic exposure (IHHE) prior to aerobic exercise on BDNF, 2023
interleukin-6 (IL-6), and C-reactive protein (CRP) blood levels in geriatric patients.
Patients and Methods: Twenty-five geriatric patients (83.1 ± 5.0 yrs, 71.1 ± 10.0 kg, 1.8 ± 0.9 m) KEYWORDS
participated in a placebo-controlled, single-blinded trial and were randomly assigned to either an Interleukin 6; C-reactive
intervention (IG) or control group (CG) performing an aerobic cycling training (17 sessions, protein; BDNF; hypoxia;
20 min·session−1, 3 sessions·week−1). Prior to aerobic cycling exercise, the IG was additionally elderly
exposed to IHHE for 30 min, whereas the CG received continuous normoxic air. Blood samples
were taken immediately before (pre-exercise) and 10 min (post-exercise) after the first session as
well as 48 h (post-training) after the last session to determine serum (BDNFS) and plasma BDNF
(BDNFP), IL-6, and CRP levels. Intervention effects were analyzed using a 2 x 2 analysis of covariance
with repeated measures. Results were interpreted based on effect sizes with a medium effect
considered as meaningful (ηp2 ≥ 0.06, d ≥ 0.5).
Results: CRP was moderately higher (d = 0.51) in the CG compared to the IG at baseline. IHHE had
no acute effect on BDNFS (ηp2 = 0.01), BDNFP (ηp2 < 0.01), BDNF serum/plasma-ratio (ηp2 < 0.01),
IL-6 (ηp2 < 0.01), or CRP (ηp2 = 0.04). After the 6-week intervention, an interaction was found for
BDNF serum/plasma-ratio (ηp2 = 0.06) but not for BDNFS (ηp2 = 0.04), BDNFP (ηp2 < 0.01), IL-6 (ηp2
< 0.01), or CRP (ηp2 < 0.01). BDNF serum/plasma-ratio increased from pre-exercise to post-training
(d = 0.67) in the CG compared to the IG (d = 0.51). A main effect of time was found for BDNFP (ηp2
= 0.09) but not for BDNFS (ηp2 = 0.02). Within-group post-hoc analyses revealed a training-related
reduction in BDNFP in the IG and CG by 46.1% (d = 0.73) and 24.7% (d = 0.57), respectively.
Conclusion: The addition of 30 min IHHE prior to 20 min aerobic cycling seems not to be effective
to increase BDNFS and BDNFP or to reduce IL-6 and CRP levels in geriatric patients after a 6-week
intervention.
The study was retrospectively registered at drks.de (DRKS-ID: DRKS00025130).
Introduction age-related shrinkage occurs in the medial temporal

(i.e. hippocampus) [2] and frontal lobes (i.e. prefrontal
Aging is associated with white and grey matter vol-
cortex) [3]. These age-related neuroanatomical changes
ume loss as well as a decline in white matter integrity
are assumed to be associated with the worsening in
[1]. More specifically, it has been shown that the
CONTACT Tom Behrendt [email protected] Department of Sport Science, Chair for Health and Physical Activity/Otto-von-Guericke University
Magdeburg, Zschokkestraße 32, Magdeburg, 39104, Germany
#
These authors share first authorship.
Supplemental data for this article can be accessed online at https://doi.org/10.1080/07853890.2024.2304650.
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been
published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 T. BEHRENDT ET AL.
cognitive performance (e.g. intelligence, memory, pro- However, BDNF blood concentration shows physio-
cessing speed, and executive functioning) [4,5]. In logical (e.g. activity- and age-dependent) and patho-
addition to changes in brain structure, a previous physiological (e.g. disease-dependent) fluctuations
study using diffusion tensor imaging tractography [31,32]. For instance, an exploratory mediation analysis
showed that age-related changes in cognitive perfor- showed that BDNFS, hippocampal volume, and spatial
mance might also be mediated by declined integrity memory function were reduced with increasing age
of the corpus callosum (i.e. central portion of the genu [33]. In addition, BDNFS was found to mediate the
and splenium-partial fibers in the right hemisphere) age-related decline in hippocampal volume, which in
[6]. Noteworthy, in patients with neurodegenerative turn promotes the age-related decline in spatial mem-
diseases (e.g. dementia), changes in brain structure ory function [33]. Further, studies have shown that
and function are more pronounced compared to BDNFP was lower in older people with pre-frailty [34]
age-matched healthy controls [7]. and frailty [35] compared to those without frailty.
Among other factors, regular and continuous phys- Diminished BDNF levels have also been found in
ical activity (e.g. strength and/or endurance training) patients with neurodegenerative or neuropsychiatric
can reduce the age-related structural and functional disorders/disease, such as Alzheimer’s disease [36–38]
deteriorations [8–11]. Brain-derived neurotrophic fac- (especially when severity of disease is progressed [39])
tor (BDNF) is considered one key neurotrophin and depression [40]. In this context, BDNFS and BDNFP
responsible for the beneficial functional and/or struc- may serve as surrogate biomarkers for assessing the
tural brain adaptations induced by physical activity success of interventions to preserve or even improve
(e.g. brain volume and integrity), facilitating socio- brain structure and function.
emotional (e.g. sleep quality and mood) and/or Interestingly, animal studies have found that acute
performance-related changes (e.g. memory and exec- and chronic exposure to intermittent hypoxia increased
utive functioning) [12–14]. In this process, the precur- BDNF protein and the BDNF messenger ribonucleic
sor protein proBDNF is cleaved to BDNF pro-peptide acid (mRNA) transcription level in various brain areas
and mature BDNF (mBDNF). While proBDNF predomi- (e.g. pons, cerebral cortex, primary motor cortex, and
nantly activates the p75-receptor and leads to apop- brain endothelial cells) [41–44]. Moreover, Ryou et al.
tosis, mBDNF mainly binds to tropomyosin related [41] showed that daily exposure to 10 cycles of inter-
kinase B (TrkB), which promotes essential processes mittent hypoxia (6 min hypoxia (fraction of inspired
such as neurogenesis, neuronal differentiation, synap- oxygen (FiO2) = 0.10) interspersed by 4 min of nor-
togenesis, neuronal survival, and long-term potentia- moxia) over a period of 21 days increased cerebrocor-
tion [15,16]. Nevertheless, it appears that there is no tical erythropoietin (EPO) and BDNF formation in
clear and strict separation between proBDNF/p75 and triple-transgenic mouse model of Alzheimer’s disease.
mBDNF/TrkB signaling pathways. Actually, it is possi- These increments were associated with improved spa-
ble that there are transitions between the two recep- tial learning and memory function. With regard to
tors and/or induced signaling pathways that human studies, exposure to intermittent or prolonged
complementarily and synergistically contribute to the hypoxia for 4 to 8 weeks (3 sessions·week−1) was shown
formation and remodeling of synaptic spines [14]. to increase cognitive performance in healthy older
Therefore, activity-induced release of BDNF [17] pro- adults [45,46] and patients with amnestic mild cogni-
motes neuroplasticity and thus regulates processes tive impairment [47]. The neuroprotective effect of
involved in learning and memory formation [16,18– intermittent hypoxic exposure is thought to be related
22]. The majority of BDNF is released in the brain to the stabilization of hypoxia-inducible factor (HIF,
with high and usually lifetime expression in the hip- especially HIF-1α) and the generation of reactive oxy-
pocampus and neocortex [23–26]. Since BDNF is gen species (ROS) [48,49]. HIF-1α activates, among oth-
assumed to cross the blood-brain barrier in both ers, the transcription of genes responsible for
directions, peripheral BDNF concentration in venous angiogenesis [50], vasodilation [51,52], glucose trans-
blood, especially in serum (BDNFS) and plasma port, and glucose metabolism [53,54]. In this regard,
(BDNFP), is suggested as a suitable surrogate bio- especially cardiovascular and metabolic adaptations to
marker for brain BDNF concentration [27,28]. This is intermittent hypoxia are assumed to protect against
supported by studies in healthy young adults reveal- neurodegeneration (e.g. by augmenting cerebral blood
ing a positive association between acute flow and vascularization and reducing cardiovascular
exercise-induced improvements in prefrontal- [29] as risk factors) [48,55]. Based on the phenomenon of
well as hippocampal-dependent [30] cognitive perfor- cross adaptations, ROS-initiated redox signaling induces
mance and increases in BDNFS. anti-oxidative and anti-inflammatory genes by activat-
Annals of Medicine 3
ing the transcription factor nuclear factor- (serum) and freely circulating BDNF (plasma). Since no
erythroid 2-related factor 2 [56,57]. Moreover, exposure study has investigated the effect of exercise or IHHE
to normobaric hypoxia is a valuable strategy to interventions on the BDNFS/P-ratio so far, we applied
enhance EPO production [58–60]. Besides its function an exploratory approach for this purpose.
in regulating erythropoiesis [61], EPO also induces
anti-oxidative and anti-inflammatory effects [62], which
could be beneficial in the context of systemic chronic Materials and methods
inflammation associated with a wide range of Participants
(age-associated) diseases, such as neurodegenerative
disease [48,63,64]. In this regard, Kiers et al. demon- A total of 38 geriatric patients aged over 70 years were
strated that continuous exposure to normobaric recruited from two inpatient full-day care facilities for
hypoxia (3.5 h at an arterial oxygen saturation of geriatric patients and assessed for eligibility to partici-
80–85%) enhanced adenosine release, resulting in an pate in this study. All patients and, if required, their
adenosine 2B receptor-dependent increase in legal guardians were informed about the aims and the
anti-inflammatory markers (i.e. interleukin (IL)-10) experimental procedure and have given their written
blood concentration and subsequent dampening of informed consent. Patients were part of a larger trial
endotoxin-induced systematic inflammatory cytokine that investigated the effect of IHHE prior to aerobic
response (i.e. tumor necrosis factor α (TNFα), IL-6, and cycling on physical and cognitive performance [70] and
IL-8) [65]. cardiovascular risk factors [72]. Based on a medium
A previous study examining BDNF secretion from effect size (Cohen’s f = 0.25), a significance level of 0.05,
mouse brain microvascular endothelial cells found that a power of 0.80, and an expected correlation between
both prolonged and intermittent hypoxia stimulated measures of 0.7, a sample size calculation was per-
BDNF expression, with the latter being more potent, formed for the whole trial for a 2 × 2 repeated mea-
possibly mediated by increased ROS formation [44]. sures ANOVA. The Dementia Detection Test performance
Since ROS formation occurs during reoxygenation, it is was chosen as the primary outcome. Accordingly, a
supposed that replacing normoxia by moderate hyper- total sample size of 22 patients was required to detect
oxia can increase the neuroprotective effect of inter- potential effects [70]. All patients included in the study
mittent hypoxia by upregulation of redox signaling met the definition of geriatric patients according to the
[63,66,67]. This method, referred to as intermittent German Society of Geriatrics, the German Society of
hypoxic-hyperoxic exposure (IHHE) [68], has already Gerontology and Geriatrics, as well as the German
been shown to be a well applicable and tolerable Group of Geriatric Institutions [73]. Therefore, geriatric
non-pharmacological intervention strategy for improv- patients were defined by geriatric multimorbidity and
ing cognitive performance [69–71] and to reduce cir- an increased age (commonly > 70 years, however, mul-
culating biomarkers of Alzheimer’s disease [71] in timorbidity is the primary criterion before calendar
geriatric patients and patients with mild cognitive age) or an age of at least 80 years in combination with
impairment. increased vulnerability. Patients were excluded if they
However, the acute and chronic effects of IHHE on were current smokers, had untreated or uncontrolled
BDNF blood concentration and inflammatory state in diseases (hypertension, coronary artery disease with
humans remain largely uninvestigated. Therefore, this unstable angina pectoris (CCS 3-4), severe heart failure
study was designed to analyze the acute and chronic (NYHA II-IV), arrhythmia, diabetes mellitus, pulmonary
effects of IHHE prior to aerobic cycling on post-exercise fibrosis), chronic obstructive pulmonary disease, cancer,
and -training levels of BDNFS and BDNFP as well as acute inflammatory disease, need for continuous or
C-reactive protein (CRP) and IL-6 in geriatric patients, intermittent ventilation or oxygenation, arterial oxygen-
respectively. It was expected that adding IHHE prior to ation saturation at rest < 93%, or simultaneously partic-
aerobic cycling would augment the exercise-induced ipated in other interventions. After excluding 5 patients
acute increase in BDNFS, BDNFP, and IL-6. Furthermore, (Leukemia (n = 1), chronic obstructive pulmonary dis-
it was hypothesized that 6 weeks of training would ease (n = 1), inability to participate (n = 3)), a total of 33
increase basal BDNFS and BDNFP as well as decrease patients participated in the present study (Figure 1).
CRP and IL-6 levels in geriatric patients receiving the
IHHE compared with those receiving sham-IHHE (i.e.
Study design
placebo control group). In addition, BDNF serum/
plasma-ratio (BDNFS/P-ratio) was calculated to assess A randomized, two-armed, controlled, and single-blinded
changes in the proportion of BDNF stored in platelets (patients’ allocation) study design was used. Prior to the
Figure 1. Flow chart of the study. BDNFS: serum brain-derived neurotrophic factor; BDNFP: plasma brain-derived neurotrophic factor; BDNFS/P-ratio:
brain-derived neurotrophic factor serum/plasma-ratio; CG: control group; COPD: chronic obstructive pulmonary disease; IG: intervention group.
start of this study, patients’ age, sex, anthropometric on human experimentations. The study was retrospec-
data, medical history, previous diagnosed disease, and tively registered at drks.de (DRKS-ID: DRKS00025130).
level of cognitive impairment (Mini-Mental State
Examination) were recorded. All patients were randomly
Intervention
assigned to an intervention group (IG, n = 16) or a con-
trol group (CG, n = 17) using stratified (Mini-Mental State Prior to the first training session, patients were famil-
Examination) and counterbalanced (1:1) randomization iarized with the environment and interventional proce-
(DatInf Randlist v. 1.5, DatInf GmbH, Tübingen, Germany). dure. Furthermore, patients’ individual level of
Blood sample collection was performed immediately resistance for the aerobic cycling training was esti-
before (pre-exercise) and 10 min after the 1st training mated as described previously [70,74]. The training
session (post-exercise) as well as 48 h after the last train- was conducted on Monday, Wednesday, and Friday for
ing session (post-training). All training sessions and data 6 weeks resulting in 17 training sessions. At the begin-
collections were conducted in the respective inpatient ning of each training session, patients of both groups
care facility. were connected to an altitude breathing therapy
The experimental protocol was approved by the device (ReOxy, Ai Mediq S.A., rue de Bitbourg,
Otto-von-Guericke University Magdeburg (No. 202/20) Luxemburg) through a face mask, inhaling a gas mix-
confirming the principles of the Declaration of Helsinki ture for 30 min while sitting on an armchair. During
this procedure, the IG was breathing intermittent centrifugation at 2000 G for 15 min. For each blood
hypoxic-hyperoxic air (IHHE), while the CG was breath- sample, 600 µL of the supernatant serum and plasma
ing normoxic air (sham-IHHE, FiO2 ~ 0.209). During the fluid were extracted and stored at −80 °C. BDNFS and
IHHE or sham-IHHE, patients’ peripheral oxygen satura- BDNFP were determined using a commercially avail-
tion (SpO2) was continuously monitored. The dose of able DuoSet ELISA kit (R&D Systems®, Wiesbaden,
the IHHE program was individually tailored, depending Germany). Genomic DNA was extracted from anticoag-
on the results of a hypoxic test, which was performed ulated venous blood (BD Vacutainer® LiHeparin, 4.0 ml,
prior the first and 10th training session [66], and the Franklin Lakes, NJ USA) collected immediately prior to
patients’ acute responses (i.e. SpO2 and pulse rate) [70]. the 1st training session. BDNF genotype was assessed
Based on the ‘SpO2 clamp’ approach [75], the external by using conventional polymerase chain reaction (PCR)
hypoxic intensity (i.e. FiO2) was automatically adjusted and restriction fragment length polymorphism analy-
to ensure that patients achieved an SpO2 of 85–88% sis. PCR amplification of the BDNF polymorphism
and 85% in the first and last three weeks, respectively. Val66Met was performed using the forward primer 5′-
Thus, patients of the IG intermittently (4–8 cycles) GCA TCC CGG TGA AAG AAA GCC CTA AC −3′ and the
received a hypoxic gas mixture (FiO2 = 0.100 − 0.140) reverse primer 5′- GCC CCT GCA GCC TTC TTT TGT GTA
for 1 to 5 min, followed by a 1 to 3.5 min exposure to AC −3′. PCR products were digested using the restric-
a hyperoxic gas mixture (FiO2 = 0.300 − 0.400). tion enzyme Enzym Eco 72i (Thermo Fisher Scientific;
Afterwards, patients of both groups participated in Waltham, MA USA). IL-6 and CRP levels were quantified
a supervised aerobic cycling training (20 min per ses- using an electro chemiluminescent assay and
sion) using a motorized cycle ergometer (MOTOmed particle-enhanced immunological turbidity assay,
viva 2 and viva 1, Reck, Betzensweiler, Germany) under respectively (COBAS® 2000, Roche Diagnostics, Basel,
normoxic conditions (without a facemask). The training Switzerland). In addition,BDNFS/P-ratio was calculated
program was designed based on current exercise rec- to assess changes in the proportion of BDNF stored in
ommendations for older adults [76] and previous stud- platelets (serum) and freely circulating BDNF
ies [74,77]. In brief, the training consisted of a 2.5 min (plasma) [14].
warm-up (i.e. passive resistance pedaling at 20 rpm),
followed by a 15 min main part (i.e. active pedaling at
Statistical analysis
30–60 rpm), and a 2.5 min cool-down (i.e. passive resis-
tance pedaling at 20 rpm). Patients’ pulse rate (i.e. prior Data analysis was conducted using JASP Statistics
to the warm-up and immediately after the main part) (Version 0.16, University of Amsterdam, Amsterdam,
and total work (kJ) were recorded for each session. Netherlands). The descriptive statistics were presented
as means and standard deviations. To compare patients’
characteristics at baseline and training variables
Blood sample collection and analysis
between the IG and CG, independent Student’s t-tests
Venous blood samples were taken by a physician from were used. Intervention effects regarding acute and
a superficial forearm vein under stasis conditions with chronic changes in BDNF, IL-6, and CRP plasma and/or
patients seated at rest at the time points mentioned serum concentration as well as BDNFS/P-ratio were
above. The blood samples were collected in two examined using an analysis of covariance (ANCOVA)
vacutainers with separated gel and coagulation activa- with repeated measures with time (acute: pre-exercise
tor (BD Vacutainer® SST TM II Advance, 8.5 ml, Franklin and post exercise; chronic: pre-exercise and
Lakes, NJ USA) to determine BDNFS, IL-6, and CRP lev- post-training) as a within-subject factor and group (IG
els as well as one vacutainer with lithium heparin (BD and CG) as a between-subject factor. In addition, the
Vacutainer® LiHeparin, 4.0 ml, Franklin Lakes, NJ USA) following covariates were entered in the statistical
to determine BDNFP level. Immediately after blood col- analyses: BDNFS and BDNFP (acute: average work per-
lection, vacutainers were swirled head down for 10 formed during the first aerobic cycling session,
times. Only for the first blood collection (i.e. MMSE-score, age, BMI, and BDNF genotype; chronic:
pre-exercise), a sample of venous blood from the MMSE-score, age, BMI, and BDNF genotype) and serum
vacutainer with lithium heparin (~ 400 µL) was filled IL-6 and CRP concentrations (acute: average work per-
into an Eppendorf tube to assess patients’ BDNF gen- formed during the first aerobic cycling session,
otype (Val66Val, Val66Met, or Met66Met). Thereafter, MMSE-score, age, BMI; chronic: MMSE-score, age, BMI).
the serum and plasma samples were rested for 30 min If the assumption of sphericity was violated,
at room temperature and for 10 min on ice, respec- Greenhouse-Geisser correction was applied. In case of
tively, before serum and plasma was separated by significant interactions or main effects, post-hoc
analyses with Bonferroni correction were performed. Table 1. Patients’ characteristics at baseline split by group
Since it was shown that the ANOVA [78,79] and t-test (intervention group (IG), control group (CG)). Values are pre-
[80,81] could be used without significant error despite sented as means ± standard deviations.
violation of homogeneity or normality assumptions, no Characteristics IG (n = 12) CG (n = 12)
alternative nonparametric tests were performed. Age [years] 82.7 ± 4.3 83.5 ± 6.0
Women n = 12 (100%) n = 10 (83%)
Differences between groups are presented as mean Height [cm] 73.4 ± 9.4 160.3 ± 10.1
differences together with 95% confidence intervals. Weight [kg] 71.2 ± 11.9 68.8 ± 10.9
Body Mass Index [cm·kg−²] 28.7 ± 2.4* 26.8 ± 3.7
When interpreting the results of intervention studies, it Mini-Mental-State-Examination 16.9 ± 8.9 14.8 ± 8.0
is recommended to consider the effect size in order to Clinical Diagnosis [n (%)]
Alzheimer’s dementia 3 (25%) 6 (50%)
clarify the practical and clinical relevance of the results Vascular dementia 1 (8%) 0 (0%)
[82–85]. Accordingly, the results of the present study Mixed types of dementia 4 (33%) 5 (42%)
Hypertension 10 (83%) 10 (83%)
were interpreted based on the effect sizes with a Diabetes mellitus type II 3 (25%) 5 (42%)
medium effect considered as meaningful. Thus, the Hypothyreosis 2 (17%) 4 (33%)
effect sizes partial eta squared (ηp2) and Cohen’s d (d) Osteoporosis 3 (25%) 4 (33%)
* Differences between groups (d ≥ 0.5).
were calculated and classified as small (ηp2 ≥ 0.01,
d ≥ 0.20), medium (ηp2 ≥ 0.06, d ≥ 0.50), and large (ηp2 ≥
0.14, d ≥ 0.80) effect [82,86,87]. d = 0.12) and after (IG = 74.0 ± 9.7 min−1, CG =
75.3 ± 10.8 min−1, d = 0.13) these sessions. By retrospec-
tively calculating the percentage of the estimated heart
Results
rate (208 − 0.7 · age [88]), patients from the IG and CG
To determine the practical relevance and generalizabil- achieved an average of 51 ± 8% and 49 ± 6% of their
ity of the effect of IHHE prior to aerobic cycling of estimated maximum heart rate at the end of each aer-
neurotrophic and inflammatory blood markers in geri- obic cycling session, respectively. During the interven-
atric patients, results were interpreted based on effect tion period, there were no injuries or adverse side
sizes (not p values) with a medium effect considered effects associated with the IHHE, sham-IHHE, or aerobic
as meaningful (i.e. ηp2 ≥ 0.06, d ≥ 0.50). cycling training except for some reports of mild dizzi-
Five out of 33 enrolled patients were excluded from ness and uncomfortable feeling caused by wearing the
the final analysis due to a low attendance rate (< 80%, facemask. The IG (Val66Val = 70%, Val66Met = 20%, and
CG: n = 3) or acute inflammatory disease (IG: n = 2). In Met66Met = 10%) and CG (Val66Val = 73%, Val66Met =
addition, there were irreversible data losses due to mea- 18%, and Met66Met = 9%) showed similar distribution
surement errors in 4 patients (e.g. blood sampling or of BDNF genotypes.
genotyping, IG: n = 2, CG: n = 2). Thus, data of 24 patients Table 2 shows the BDNFS, BDNFP, IL-6, and CRP
(average attendance rate: IG = 99 ± 2%; CG = 94 ± 8%) blood concentrations as well as BDNFS/P-ratio before
were included in the final analysis. Concerning the (pre-exercise) and 10 min after (post-exercise) the first
chronic effects on BDNFS, BDNFP, and BDNFS/P-ratio, data intervention session as well as 48 h after the last inter-
of one patient could not be included in the analysis vention session (post-training) together with the results
due to irreversible data loss (CG: n = 1). No differences in of the ANCOVA with repeated measures. Descriptive
patients’ cognitive ability (MMSE Score), number of dis- data are shown in Figure 2. Results of the post-hoc
eases, and demographic as well as anthropometric char- tests are shown in Supplementary Tables 1 and 2.
acteristics were found between IG and CG (d ≤ 0.45), With regard to the acute effects, the statistical anal-
except the body mass index (T22 = 1.438, p = .164, yses revealed no interaction or main effect of group
d = 0.59; MD = 1.27 kg/m2 (95% CI = −4.46 to 0.81 kg/m2); but a main effect of time for BDNFS and BDNFP.
shown in Table 1). The minimum SpO2 was lower in the However, post-hoc analyses indicated no within-group
IG (84.3 ± 2.3%) during the IHHE than in the CG differences from pre- to post-exercise for BDNFS (IG =
(94.0 ± 1.8%) during the sham-IHHE (T22 = 11.473, p < 2588.3 pg/ml (95% CI = −3074.4 to 8250.9 pg/ml),
.001, d = 4.68; MD = 9.71% (95% CI = 0.84 to 7.95%)), p = 1.000, d = 0.23; CG = 1303.4 pg/ml (95% CI = −4359.0
whereas there were no differences between groups for to 6966.0 pg/ml), p = 1.000, d = 0.12) and BDNFP (IG:
maximum SpO2 (d = 0.37; IG = 96.8%, CG = 96.2%). With −148.2 pg/ml (95% CI = −1107.1 to 810.6 pg/ml),
respect to the aerobic cycling training, there were no p = 1.000, d = 0.18; CG: −88.8 pg/ml (95% CI = −1047.6 to
differences between groups for average work generated 870.1 pg/ml), p = 1.000, d = 0.11). No interaction or main
during the 20 min cycling sessions (IG = 99.3 ± 37.0 kJ, effects were found for acute changes in BDNFS/P-ratio
CG = 117.9 ± 51.4 kJ, d = 0.42) and the average pulse rate and IL-6. Furthermore, no interaction or main effect of
before (IG = 71.5 ± 9.9 min−1, CG = 72.6 ± 8.4 min−1, time but a main effect of group was found for CRP.
Between-group post-hoc analyses showed a moderate
brain-derived neurotrophic factor serum blood concentration (BDNFS), brain-derived neurotrophic factor plasma blood concentration (BDNFP), brain-derived neurotrophic factor serum/
Table 2. Acute and chronic effects of intermittent hypoxic-hyperoxic exposure (IHHE, intervention group (IG)) and sham-IHHE (control group (CG)) prior to aerobic cycling on
F1,17 = 0.279, p = .604,
F1,17 = 1.589, p = .223,
F1,17 = 0.659, p = .428,
F1,19 = 2.237, p = .151,
F1,19 = 0.409, p = .530,

Main time effect
effect for higher CRP blood concentrations in the CG
at pre-exercise (0.96 mg/l (95% CI = −1.50 to 3.42 mg/l),
ηp² = 0.02
ηp² = 0.09
ηp² = 0.04
ηp² = 0.11
ηp² = 0.02
p = 1.000, d = 0.51), whereas there was a trend for a
moderate effect post-exercise (0.84 mg/l (95% CI = −1.62
to 3.29 mg/l), p = 1.000, d = 0.45).
Main group effect
Concerning the chronic effects, no interaction or
.886, ηp² < 0.01
.588, ηp² = 0.02
.459, ηp² = 0.03
.920, ηp² < 0.01
.383, ηp² = 0.04

F1,17 = 0.021, p =
F1,17 = 0.304, p =
F1,17 = 0.073, p =
F1,19 = 0.010, p =
F1,19 = 0.798, p =
main effects were found for BDNFS. While there was no
ANCOVA
interaction or main effect of group, a main effect of

time was found for training-related changes in BDNFP.
Within-group post-hoc analyses for the IG and CG indi-
Group × time interaction
F1,17 = 0.666, p = .426,
F1,17 = 0.135, p = .718,
F1,17 = 1.045, p = .321,
F1,19 = 0.003, p = .960,
F1,19 = 0.159, p = .695,

cated a reduction in BDNFP by 46.1 ± 33.5% (-577.7 pg/
ml (95% CI = −1268.3 to 112.9 pg/ml), p = .139, d = 0.73)
ηp² = 0.04
ηp² < 0.01
ηp² = 0.06
ηp² < 0.01
ηp² < 0.01

and 24.7 ± 72.9% (-451.5 pg/ml (95% CI = −1174.4 to
271.3 pg/ml), p = .478, d = 0.57), respectively. For the
plasma-ratio (BDNFS/P-ratio), interleukin-6 (IL-6), and C-reactive protein (CRP). Values are presented as means ± standard deviations.
training-related changes in BDNFS/P-ratio, there was an

interaction but no main effects. Within-group post-hoc
22775.0 ± 4513.2
25845.5 ± 5439.2
522.6 ± 308.7
687.5 ± 706.8
Post-training
analysis for the CG revealed an increase in BDNFS/P-ratio

62.6 ± 43.9
105.3 ± 91.3
4.91 ± 2.05
4.62 ± 1.90
1.79 ± 1.28
3.23 ± 4.11
from pre-exercise to post-training by 91.3 ± 128.8 (48.7

(95% CI = −16.8 to 114.2), p = .243, d = 0.67), whereas
no changes occurred in the IG (16.9 (95% CI = −45.7 to
F1,17 = 2.293, p = .148,
F1,17 = 1.616, p = .221,
F1,17 = 0.286, p = .600,
F1,18 = 0.049, p = .827,
F1,18 = 0.094, p = .763,
79.5), p = 1.000, d = 0.23). In addition, between-group

Main time effect
post-hoc analysis indicated a greater BDNFS/P-ratio in

ηp² = 0.12
ηp² = 0.09
ηp² = 0.02
ηp² < 0.01
ηp² < 0.01
CG compared to IG at post-training (31.1 (95%

CI = −40.3 to 102.39), p = 1.000, d = 0.54). There was no
interaction or main effect for CRP. Furthermore, there
was no interaction or main effect of group, but a main
F1,17 = 0.455, p = .509,
F1,17 = 0.053, p = .821,
F1,17 = 0.021, p = .885,
F1,18 = 0.141, p = .712,
F1,18 = 1.173, p = .293,

Main group effect
effect of time for IL-6. However, within-group post-hoc

ANCOVA
analyses revealed no training-related changes in IL-6

ηp² = 0.03
ηp² < 0.01
ηp² < 0.01
ηp² < 0.01
ηp² = 0.06
concentration for the IG (-0.43 ng/l (95% CI = −1.39 to

0.52 ng/l), p = 1.000, d = 0.22) and CG (-0.46 ng/l (95%
CI = −1.41 to 0.49 ng/l), p = 1.000, d = 0.23).
Group × time interaction
F1,17 = 0.211, p = .652,
F1,17 = 0.016, p = .902,
F1,17 < 0.001, p = .986,
F1,18 = 0.011, p = .917,
F1,18 = 0.810, p = .380,
Discussion
ηp² = 0.01
ηp² < 0.01
ηp² < 0.01
ηp² < 0.01
ηp² = 0.04
The results of the present study indicate that the

addition of 30 min IHHE prior to 20 min aerobic
cycling has no acute or chronic effect on BDNFS,
33358.3 ± 13396.4
32875.0 ± 10438.9
BDNFP, IL-6, and CRP levels in geriatric patients.

Post-exercise
935.0 ± 509.8
1060.7 ± 799.6
50.2 ± 46.9
46.1 ± 27.1
5.54 ± 2.26
5.23 ± 2.15
1.83 ± 1.23
2.63 ± 2.06
ANCOVA: analysis of covariance with repeated measures.
Interestingly, while the BDNFS/P-ratio was not affected

by a single session, there was a training-related effect
after the 6-week intervention. As a further result, it
was shown that regardless of the IHHE treatment,
31283.3 ± 13065.2
31058.3 ± 6095.5
1155.7 ± 1232.4
BDNFP was reduced in both groups after the 6-week

1077.0 ± 111.0
Pre-exercise
49.4 ± 47.5
50.5 ± 34.1
5.29 ± 2.09
5.13 ± 1.85
1.00 ± 1.18
2.22 ± 0.30
intervention period.
Based on the findings of animal [41] and human
[89] studies, hypoxia-induced secretion and/or expres-
sion of neurotrophic factors, such as BDNF, has been
Group
proposed as a possible mechanism to explain the ben-

CG
CG
CG
CG
CG
IG
IG
IG
IG
IG
eficial neurocognitive effects of interventions applying

BDNFP [pg/ml]
BDNFS [pg/ml]
intermittent hypoxia [48,49,90]. There is currently no

BDNFS/P-ratio
CRP [mg/l]
IL-6 [ng/l]
Outcome
study available that has examined the acute and/or

chronic effects of IHHE prior to aerobic exercise on
Figure 2. Acute and chronic effects of intermittent hypoxic-hyperoxic exposure (IHHE, intervention group) and sham-IHHE (control
group) prior to aerobic cycling on (A) brain-derived neurotrophic factor serum blood concentration (BDNFS), (B) brain-derived
neurotrophic factor plasma blood concentration (BDNFP), (C) brain-derived neurotrophic factor serum/plasma-ratio (BDNFS/P-ratio),
(D) interleukin-6 (IL-6), and (E) C-reactive protein (CRP). Values are presented as individual data points and medians (horizontal
lines) with the 25th and 75th percentiles. * d > 0.50 vs. pre-exercise, # d > 0.50 vs. intervention group.
BDNFS and BDNFP in humans. However, the data of the 25 °C) on BDNFS during a self-paced 30 min time trial
present study indicate that the previously observed in young healthy trained males [92]. The authors have
hypoxia-induced increase in BDNF expression [89] does found that BDNFS increased immediately after exer-
not seem to be possible with the applied IHHE proto- cise, regardless of hypoxia or temperature. Noteworthy,
col performed prior to aerobic cycling in our sample subjects exhibited increased blood lactate concentra-
of geriatric patients. tion and decreased power output in hypoxia com-
Regarding the acute effects, previous studies have pared to normoxia. Thus, it appears that hypoxia can
examined the influence of a single aerobic exercise modulate metabolic and molecular responses to aero-
session under normobaric hypoxia (i.e. continuous bic exercise, as evidenced by equal (i.e. BDNFS or
hypoxic training) on BDNF blood concentration [91,92]. BDNFP) and enhanced (i.e. blood lactate concentra-
Piotrowicz et al. showed that BDNFP increased imme- tion) physiological responses at lower levels of
diately after an incremental cycling test until exhaus- mechanical work (i.e. reduced power output) com-
tion by 29.3% and 50.0% under normoxia and pared to normoxia. In this regard, studies suggested
normobaric hypoxia (FiO2 = 0.147), respectively, in that blood lactate is involved in the regulation of
young cyclists [91]. Although the relative increase in BDNF blood concentration [93–96] and associated
BDNFP seemed to be higher in the hypoxia session, with greater improvements in executive functions
there were no differences between conditions. [97,98]. Considering that blood lactate is an indicator
Interestingly, blood lactate concentration was higher, of exercise intensity, the absence of an acute increase
while maximal power output and oxygen consump- in BDNFS and/or BDNFP in the present study could be
tion were lower under hypoxia compared to normoxia. due to the low intensity of the used aerobic cycling
Similar results were reported by Van Cutsem et al. exercise [99,100] and/or the characteristics of the
examining the effect of hypoxia and ambient tem- hypoxic stimulus administered (i.e. the hypoxic dose
perature (i.e. exercising under (i) normoxia at 15 °C, (ii) (e.g. intensity/severity, duration, density, frequency) or
normoxia at 25 °C, (iii) hypoxia (3800 m, FiO2 ~ 0.132) method (e.g. passive vs. active application)) [101].
at 15 °C, and (iv) hypoxia (3800 m, FiO2 ~ 0.132) at Indeed, previous studies have shown that BDNFS
increased after acute continuous aerobic cycling of Furthermore, Becke et al. demonstrated that 2 weeks
30 min at 60% of individuals heart rate reserve [102] of intermittent hypoxic exposure (12 sessions, 60 min·-
and 40 min at 65–75% of individuals maximum heart session−1, 5 min·period−1, SpO2 = 85–80% (simulated
rate [103] in older adults. Meta-analyses indicate that altitude was manually adjusted between 4000 and
the exercise intensity [104] and duration [105] are 5000 m)) resulted in decreased BDNFP but not BDNFS
potential factors influencing the effect of acute exer- levels compared to a normoxic control group in
cise on BDNF blood concentration. In particular, it was healthy young adults [110]. In a further study, per-
suggested that acute high-intensity exercise increases forming prolonged hypoxic exposure (90 min, SpO2 =
BDNFS compared with non-exercise or low-intensity progressively decreased from 90 to 80%) prior to aer-
exercise but not with moderate-intensity exercise obic cycling (30 min, load = progressively increased
[104]. In addition, exercise sessions with a duration of from 65 to 75% of maximum heart rate) over 4 weeks
> 30 min lead to a greater acute increase in BDNF (3 sessions·week−1), no additive effect on BDNFS were
blood concentration than exercise sessions lasting ≤ observed compared to a normoxic control group in
30 min [105]. The aerobic exercise sessions in the cur- healthy older adults aged 60 to 75 years [45]. Previous
rent study lasted 20 min and patients from the IG and studies revealed that the magnitude and even the
CG achieved an average of 51 ± 8% and 49 ± 6% of direction (i.e. harmful or beneficial) of the effects elic-
their estimated maximum heart rate, which corre- ited by hypoxia largely depend on the hypoxic dose
sponds to a low exercise intensity [106]. Therefore, it [58,101,111,112]. Moderate- to low-dose hypoxia trig-
can be assumed that the exercise intensity and/or gers redox signaling, which activates transcription fac-
duration was not sufficient to induce a detectable tors initiating beneficial effects (e.g. expression of
increase in BDNF blood concentration. anti-inflammatory enzymes and reduction of the
Hubold et al. [107] and Chroboczek et al. [108] pro-inflammatory response [65,113]), whereas a more
examined the effect of a brief hypoxic exposure intense hypoxic dose provokes toxic levels of ROS for-
(30 min of continuous normobaric hypoxia) on BDNFP mation causing harmful oxidative stress and inflamma-
levels in young healthy males in comparison to nor- tion [63,114]. In this regard, increased IL-1 receptor
moxic control. Interestingly, the results from Hubold antagonist, IL-6, and CRP blood levels have been
et al. indicate that brief hypoxia (SpO2 = 75%) alleviate observed in healthy humans exposed to sustained
the time-dependent decrease in BDNFP resulting in a hypobaric hypoxia at high altitudes (3458 to 8848 m)
higher BDNFP concentration 90 min after the acute for 3 days to 8 weeks [115,116]. Moreover, the results of
exposure when plasma glucose was held stable an animal study suggest that injection of high doses
between 4.5 and 5.5 mmol/l by euglycemic clamp of lipopolysaccharide, an endotoxin and proinflamma-
[107]. Chroboczek et al. showed an increase in BDNFP tory agent, results in an increased level of inflamma-
level 5–6 min after acute exposure to hypoxia (FiO2 = tory markers in the hippocampus and a decrease in
0.130) compared to baseline, which was not seen in long-term potentiation and BDNF expression in adult
the normoxic control condition [108]. Furthermore, male mice [117]. Indeed, Becke et al. and Li et al.
blood cortisol concentration was decreased after the observed an increase in lymphocytes, granulocytes,
normoxic control compared to the hypoxia condition and IL-1β, respectively, leading to the assumption that
[108]. Nevertheless, it must be taken into account that the applied hypoxic dose was too high, and thus
the order in which the subjects performed the condi- caused systemic inflammation that possibly decreased
tions was not randomized (i.e. all subjects started with BDNF expression [109,110]. In the current study, no
the control condition) and that all subjects had per- within- or between-group differences were found for
formed a cognitive task immediately before blood col- IL-6 and CRP blood levels, suggesting that
lecting, which could have influenced BDNFP levels hypoxia-induced systemic inflammation may not have
[108]. Studies investigating the effect of prolonged been occurred. Perhaps, these contradictory results
hypoxic exposure compared to normoxic control for at could be explained by differences in the hypoxic dose.
least 72 h on BDNF have shown contrasting results In this regard, Li et al. used prolonged exposure to
[89,109]. For instance, Li et al. have found a decrease hypobaric hypoxia (i.e. arrival to high altitude), whereas
in BDNFS on the fifth day after arrival to high altitude patients in the present study were exposed to inter-
(3900 m, average arterial blood oxygenation saturation mittent normobaric hypoxia and hyperoxia (i.e. IHHE)
= 88.7 to 89.5%) in highly trained and untrained indi- [109]. Furthermore, Becke et al. performed 12 sessions
viduals [109], while Helan et al. reported an increase in of intermittent hypoxic exposure within 2 weeks, while
BDNFS following the exposure to an FiO2 of 0.150 inter-session frequency (i.e. number of sessions across
(~ 2800 m) for 72 h in healthy volunteers [89]. a distinct time interval) and density (i.e. distribution of
sessions across a distinct time interval with regard to IL-8 and IL-10 [113]. In contrast, no changes in CRP and
recovery time in-between the sessions) were lower in other inflammatory biomarkers (e.g. TNFα) were
the current study (i.e. 3 sessions·week−1) [110]. However, observed after 8 weeks of intermittent hypoxic exposure
other factors such as genotype, physical capacity, (7 cycles, 5 min normobaric hypoxia (SpO2 ~ 75%) inter-
nutritional status, metabolic or neurological impair- spersed with 3 min normoxia, 3 sessions·week−1) in over-
ments and/or age [58,118–122] are thought to influ- weight/obese individuals [130] or 3 weeks of IHHE (4
ence the individual acute responses and/or adaptations cycles, 5 min normobaric hypoxia (FiO2 = 0.120) inter-
to hypoxia (i.e. dose-response relationship) in addition spersed with 3 min of normobaric hyperoxia (FiO2 =
to the intensity, duration, frequency, density, and type 0.330)) in healthy older adults aged 65 to 75 years and
of hypoxic stimulus. those with mild cognitive impairment [71]. Furthermore,
Interestingly, the present study has found that the when combining normobaric hypoxia with resistance
BDNFS/P-ratio increased in the CG compared to the IG exercise, no additive effects on IL-8, IL10, and CRP blood
after the 6-week intervention. While BDNFS reflects to concentration as well as the IL-6/IL-10-ratio were
> 95% the amount of BDNF stored in platelets, which observed after 24 weeks (3 sessions·week−1, 30 min·ses-
is released due to degranulation during the clotting sion−1, SpO2 ~ 90%) in older adults aged 65 to 75 years
process [123], BDNFP mirrors the freely circulating por- [131]. However, after the intervention, IL-8 and CRP
tion of peripheral BDNF. Although the origin of BDNFP blood concentrations were reduced in participants who
is not completely understood, potential sources are performed resistance training either in normoxia or nor-
vascular endothelial [124] and skeletal muscle cells mobaric hypoxia compared with an inactive control
[125], macrophages, lymphocytes [126,127], and, to an group [131]. The anti-inflammatory effect of physical
substantial extent, neurons and glia cells of the central training in older people is well known, although the
nervous system [23,24,27]. An increased BDNFS/P-ratio exact mechanisms are complex and not yet fully under-
could indicate that (i) the relative amount of BDNF stood [132,133]. This training-related effect is partly
stored in platelets was increased and/or (ii) the relative mediated by the acute expression of IL-6 from contract-
amount of freely circulating BDNF was slightly ing skeletal muscle fibers, as physiological concentra-
decreased in the CG. Although somewhat surprising, tions of IL-6 stimulates the expression of anti-inflammatory
the BDNFS/P-ratio was not affected in the IG suggesting cytokines (e.g. IL-10) and inhibit the formation of
that IHHE might have influenced the effect of an aer- pro-inflammatory cytokines (e.g. TNFα) [134,135]. The
obic training on the relative proportion of stored to acute exercise-induced release of IL-6 depends on the
freely circulating BDNF in peripheral blood. These type of exercise, the intensity, the duration, and the
results might be partially related to potential hemato- mass of recruited skeletal muscles [136]. In the present
logic changes (e.g. reduced plasma volume [128]) that study, no acute increase in IL-6 was detected after the
may have occurred as a result of the IHHE interven- first intervention session. Therefore, it can be assumed
tion. However, to the best of the authors’ knowledge, that the aerobic exercise program was not sufficient to
no study has investigated the effect of physical activity elicit anti-inflammatory effects, which might explain the
or intermittent hypoxia on BDNFS/P-ratio so far. unchanged IL-6 and CRP blood concentrations after the
Therefore, the exact reasons for the change in 6-week intervention period. With regard to the
BDNFS/P-ratio and its potential implications in the con- anti-inflammatory effect of IHHE, exposure to intermit-
text of the effect of IHHE on health-related outcomes tent hypoxia can trigger the transcription and produc-
in geriatric patients cannot be clearly elucidated at tion of anti-inflammatory and neuroprotective genes,
this time. As a consequence, further investigations such as EPO. Wojan et al. demonstrated that eight 4-min
should be carried out to clarify the potential underly- cycles of intermittent normobaric hypoxia (FiO2 =
ing mechanisms of intra- and inter-individual molecu- 0.104 ± 0.02, corresponding to a total duration of 32 min
lar responses (in particular BDNF secretion and/or at an SpO2 of ≤ 83%) represent the shortest protocol to
expression) to intermittent hypoxia and hyperoxia. increase serum EPO level in healthy individuals [59].
With regard to CRP and IL-6 blood concentrations, Certainly, the IHHE program used in the present study
the effect of intermittent hypoxia on inflammatory bio- did not correspond to the lowest dose necessary to
markers in older adults has been scarcely investigated induce a hypoxia-related increase in serum EPO level.
[68,129]. Timon et al. reported that a 24-week interven- Therefore, it might be possible that the selected IHHE
tion using prolonged hypoxic exposure (FiO2 = 0.161 for dose was too low to sufficiently increase transcription
45 min, 3 sessions·week−1) decreased CRP blood concen- and production of anti-inflammatory genes.
tration in healthy older adults aged 65 to 75 years com- As a further result, BDNFP decreased after the 6-week
pared to a normoxic control group, with no changes in intervention in both groups regardless of IHHE. In
contrast, a meta-analysis suggested that low- to investigating Caucasian populations [151,152].

moderate-intensity aerobic training does not evoke a However, due to the small sample size a subgroup
change in BDNF blood concentration in older healthy analysis to investigate the effect of the BDNF geno-
adults aged ≥ 60 years [137]. However, due a limited num- type on changes in BNDFS and BNDFP was not feasible.
ber of studies concerning the impact of aerobic training Second, we did not measure further potentially rele-
on BDNF blood concentration, specifically in older adults, vant pro- and anti-inflammatory blood markers, such
no clear conclusion can be drawn. Indeed, previous ran- as TNFα and IL-10. It was shown that aerobic exercise
domized controlled trials in this field showed contradic- (cycling for 3 h) and recombinant human IL-6 infusion
tory findings demonstrating increased [138], unchanged inhibited endotoxin-induced TNFα expression [153].
[139–141], and decreased [142] BDNF blood levels. The Furthermore, it was previously shown that short-term
discrepancy between these results indicates that BDNF hypoxia dampens the pro-inflammatory response
blood concentration probably dependent on multiple fac- during systemic inflammation due to stimulatory effect
tors modulating BDNF expression and release in a com- of adenosine on IL-10 mediated through the adenos-
plex manner [17]. For instance, BDNFS level was lower in ine 2B receptor [65]. This should be considered in
females with anorexia nervosa, whereas it was higher in future studies. Hence, no conclusions can be drawn
obese females [143] and female patients newly diagnosed regarding the effect on other potential pro- and
with type 2 diabetes mellitus [122] compared to healthy anti-inflammatory markers that were not analyzed in
normal-weight females. Furthermore, previous this study. Third, all patients in this study had several
cross-sectional studies indicated that the basal BDNF level chronic diseases and most of the patients had cogni-
is negatively correlated with maximal oxygen uptake tive impairments/diseases (e.g. dementia, mild cogni-
[144,145], heart rate reserve [145], and daily physical activ- tive impairment). In this context, although we included
ity level [146,147], whereas it is positively correlated with patients’ cognitive status (i.e. MMSE-score) as a covari-
body mass index, total cholesterol level, triglyceride level ate in the statistical analyses, it cannot be ruled out
[145], and sedentary activities (e.g. average television time that different neurodegenerative processes could have
[147]). In summary, these results suggest that basal blood influenced the results. Therefore, the current results
BDNF concentration may be related to, e.g. a person’s cannot be generalized to healthy individuals and/or
metabolic status and disorders, fitness level, and level of individuals without cognitive impairment and/or
daily physical activity. In this regard, there is convincing multimorbidity.
evidence that aerobic training can improve glucose
metabolism and aerobic capacity in adults aged ≥ 70 years
Conclusion
[76,148]. Although the duration of intervention in these
studies was at least 9 weeks, it can be assumed that the In conclusion, the current study showed that the addition
patients in the current study improved their glucose of 30 min IHHE prior to 20 min aerobic cycling is not effec-
metabolism and/or aerobic capacity, which could be tive to increase BDNFS or BDNFP in geriatric patients,
related to the reduction in basal blood BDNF concentra- either immediately after a single session or after the
tion. However, the limited number and discrepancy 6-week training period. Furthermore, the applied interven-
between previous results as well as the lack of evidence tion did not increase anti-inflammatory and/or decrease
regarding intermittent hypoxia-hyperoxia induced effects pro-inflammatory markers as indicated by no acute and
in the present study emphasize the necessity for further chronic changes in IL-6 and CRP blood concentration.
research on the effect of exercise, training, and intermit- Therefore, other hypoxia-induced mechanisms might have
tent hypoxia and/or hyperoxia on BDNF blood concentra- been responsible for the improvements in cognitive func-
tion and the potential underlying mechanisms. tion demonstrated in previous studies examining the
This study is not without limitations that must be effect of 3- to 8-week intermittent hypoxic interventions
considered. The first limitation is the small sample size [45–47,69–71]. Nevertheless, the results show that IHHE
(n = 12 per group). In this regard, large variations in was well tolerated by geriatric patients without showing
basal BDNFP can be observed, evidenced by the large adverse effects. As previous studies have shown that IHHE
standard deviations of BDNFP blood concentration in can improve physical and cognitive performance and
the current and previous studies [149]. In addition, evi- reduce cardiometabolic risk factors in older adults, this
dence suggested that the BDNF met allele is recog- method could be a promising adjuvant intervention strat-
nized to be associated with lower activity-dependent egy especially for geriatric patients. In addition, this study
secretion of BDNF [150]. Indeed, the BDNF genotype reports for the first time that IHHE prior to aerobic cycling
distribution among patients from the IG and CG is might affect training-induced changes in the BDNFS/P-ratio
consistent with previous cross-sectional studies in geriatric patients. However, the underlying mechanisms
and potential clinical effects are still unknown and require Martin Behrens http://orcid.org/0000-0003-1980-3260
further investigation. Therefore, further studies are needed Oleg S. Glazachev http://orcid.org/0000-0001-9960-6608
Tanja Brigadski http://orcid.org/0000-0001-9816-3964
to explain the mechanisms underlying this finding, such
Volkmar Leßmann http://orcid.org/0000-0002-6863-323X
as (i) augmented cerebral blood flow (i.e. by increased Lutz Schega http://orcid.org/0000-0003-0421-0796
endothelial nitric oxide production and angiogenesis), (ii)
reduced oxidative stress (i.e. by Nrf2-activated antioxidant
genes), and/or (iii) improved energy metabolism (i.e. by Data availability Statement
glycolytic enzymes and glycose transporters) [48,55,63]. The raw data supporting the conclusions of this article will
be made available by the authors on reasonable request.
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Annals of Medicine

2024, VOL. 56, NO. 1, 2304650

Brain-Derived neurotrophic factor and inflammatory biomarkers are

ABSTRACT ARTICLE HISTORY

Introduction age-related shrinkage occurs in the medial temporal

Between-group post-hoc analyses showed a moderate

F1,17 = 0.279, p = .604,

F1,17 = 1.589, p = .223,

F1,17 = 0.659, p = .428,

F1,19 = 2.237, p = .151,

F1,19 = 0.409, p = .530,

.886, ηp² < 0.01

.588, ηp² = 0.02

.459, ηp² = 0.03

.920, ηp² < 0.01

.383, ηp² = 0.04

interaction or main effect of group, a main effect of

F1,17 = 0.135, p = .718,

F1,17 = 1.045, p = .321,

F1,19 = 0.003, p = .960,

F1,19 = 0.159, p = .695,

ηp² < 0.01

ηp² < 0.01

ηp² < 0.01

training-related changes in BDNFS/P-ratio, there was an

analysis for the CG revealed an increase in BDNFS/P-ratio

from pre-exercise to post-training by 91.3 ± 128.8 (48.7

F1,17 = 1.616, p = .221,

F1,17 = 0.286, p = .600,

F1,18 = 0.049, p = .827,

F1,18 = 0.094, p = .763,

79.5), p = 1.000, d = 0.23). In addition, between-group

post-hoc analysis indicated a greater BDNFS/P-ratio in

ηp² < 0.01

ηp² < 0.01

CG compared to IG at post-training (31.1 (95%

F1,17 = 0.053, p = .821,

F1,17 = 0.021, p = .885,

F1,18 = 0.141, p = .712,

F1,18 = 1.173, p = .293,

effect of time for IL-6. However, within-group post-hoc

analyses revealed no training-related changes in IL-6

ηp² < 0.01

ηp² < 0.01

ηp² < 0.01

concentration for the IG (-0.43 ng/l (95% CI = −1.39 to

F1,17 = 0.016, p = .902,

F1,17 < 0.001, p = .986,

F1,18 = 0.011, p = .917,

F1,18 = 0.810, p = .380,

ηp² < 0.01

ηp² < 0.01

ηp² < 0.01

The results of the present study indicate that the

BDNFP, IL-6, and CRP levels in geriatric patients.

Interestingly, while the BDNFS/P-ratio was not affected

BDNFP was reduced in both groups after the 6-week

proposed as a possible mechanism to explain the ben-

eficial neurocognitive effects of interventions applying