Edited by: Jee Hyun Kim, Florey Institute of Neuroscience and Mental Health, Australia
Reviewed by: Mina M. Rizk, Columbia University, United States; Mustafa Uǧurlu, Ankara Atatürk Eǧitim ve Araştirma Hastanesi, Turkey
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It is well established that the volume of the human brain decreases in normal aging. However, accelerated hippocampal and cortical atrophy may be an indicator of the development of mild cognitive impairment or dementia in older adults (Driscoll et al.,
Cardiorespiratory fitness (CRF) has been proposed as a factor which may attenuate age-related brain atrophy (Hayes et al.,
Anxiety and depression have been linked to reduced brain volumes (Mah et al.,
The aim of the present study was to investigate the independent and joint associations of concurrent changes in eCRF and symptoms of anxiety and depression over a period of 12 years with brain parenchymal fraction (BPF), which is an estimate of structural brain reserves (Vagberg et al.,
Data was collected from the Nord-Trøndelag Health Study (HUNT), a large population-based health survey from the Nord-Trøndelag County in Norway (Krokstad et al.,
To be included in the HUNT magnetic resonance imaging (MRI) study, a sub-study in HUNT3, participants were required to have participated in HUNT1,−2, and−3, be between 50 and 65 years of age at inclusion, live within 45 min traveling distance from the location of the MRI examination, and not have standard MRI contraindications such as body weight above 150 kg. Of 1,494 invited participants, 1,088 (73%) agreed to participate in the study, and 1,006 (64.5%, 530 women) had successful MRI examinations and were defined as MRI participants. For details on inclusion and characteristics of participants, non-participants, and non-invited see Honningsvag et al. (
This study was approved by the HUNT study board of directors and the Helse Midt-Norge Regional Ethics and Health Research Committee (REK midt). All participants were legally competent adults, and gave their written informed consent.
Brain MRI was performed using a 1.5 T GE Signa HDx 1.5 T MRI scanner, equipped with an eight-channel head coil (GE Healthcare) and software version pre-14.0M4. All participants underwent the same scan protocol, for details see Haberg et al. (
MRI data was analyzed with FreeSurfer V5.3.0 (Fischl and Dale,
Intracranial volume (ICV) was estimated based on a combination of T1 and T2 images using an automated version of the reverse brain mask method (Keihaninejad et al.,
A previously validated non-exercise prediction model (Nauman et al.,
To assess change in eCRF, participants were dichotomized into “low” and “high” eCRF groups based on sex- and age- (≤46 or >46 years at HUNT2, ≤59 or >59 years at HUNT3) specific medians of the eCRF distribution. The participants were then stratified into four eCRF change groups: “remained low” (“low” at both HUNT2 and HUNT3), “decreased” (“high” at HUNT2, “low” at HUNT3), “increased” (“low” at HUNT2, “high” at HUNT3), and “remained high” (“high” at both HUNT2 and HUNT3). For greater statistical power, the continuous change variable delta eCRF (ΔeCRF) was calculated by subtracting eCRF at HUNT2 from eCRF at HUNT3 for each participant. Whereas the categorical change variable provides a relative measure of eCRF change dependent on the age- and sex-specific median, the continuous change variable provides data on absolute change in ml/kg/min from HUNT2 to HUNT3.
Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). The HADS is a self-assessment scale developed in 1983 by Zigmond and Snaith (
The HADS consists of 7 items that cover anxiety symptoms (HADS-A) and 7 items that cover depressive symptoms (HADS-D), giving a total of 14 items. Each subscale item has a 4-point Likert scale ranging from 0 (no symptom) to 3 (highest symptom level), with a maximum score of 21 on each scale indicating the highest symptom load. Participants who had responded to <5 questions on either the HADS-A (HUNT2
Based on the cut-off of ≥8 on the HADS-A and HADS-D scale, participants were classified into “low” (< 8) and “high” (≥8) HADS-categories at HUNT2 and HUNT3. Next, four HADS change groups were created: “remained low” (“low” at both HUNT2 and HUNT3), “improved” (“high” at HUNT2, “low” at HUNT3), “worsened” (“low” at HUNT2, “high” at HUNT3), and “remained high” (“high” at both HUNT2 and HUNT3). For greater statistical power, we also calculated delta HADS-A and HADS-D (ΔHADS-A and ΔHADS-D) by subtracting HADS-scores at HUNT2 from HADS-scores at HUNT3. Whereas the categorical HADS change variables provide a relative measure of HADS change as they depend on the cut-off for clinically relevant symptoms of anxiety and depression, the continuous change variables provide data on absolute change in HADS score from HUNT2 to HUNT3.
Forty-five participants were excluded from further analyses due to brain pathology, and 50 participants were excluded due to failed or incorrect FreeSurfer processing. Further, 160 participants were excluded due to missing data on eCRF or HADS. The final sample comprised 751 participants (390 women) with a mean age of 58.9 years (range 50–67) at the time of the HUNT MRI examination, and with a mean time of 11.8 ± 0.2 years between HUNT2 and HUNT3.
Descriptive statistics were used to assess study sample characteristics for the four categorical change in eCRF groups. Pearson's correlation (
To assess the joint associations of changes in eCRF and HADS, we investigated the association of ΔeCRF with brain volumes, stratified by categorical change in HADS-A and HADS-D. This allowed us to assess the influence of changes in eCRF on brain volumes among different strata of HADS change. Interaction between categorical measures of eCRF and HADS could not be assessed due to low statistical power. Thus, we investigated interaction on an additive scale between ΔeCRF and ΔHADS on brain volumes. In additional analyses, we assessed the independent associations of changes in eCRF and HADS with brain volumes. Here, ΔeCRF, ΔHADS-A, and ΔHADS-D were included in one model, and categorical measures of change in eCRF, HADS-A, and HADS-D were included in another model. Finally, in order to better capture areas in the cortex that may be associated with changes in eCRF and HADS, we performed analyses with cortical thickness and area. Here, General Linear Models (GLMs) were fitted at each vertex across the cortical surface. Individual surface maps were smoothed with a full-width-half-maximum Gaussian kernel of 25 mm, averaged across participants (Fischl and Dale,
All statistical analyses were performed with IBM SPSS Version 25 for Windows (SPSS Inc, Los Angeles, USA). A
Study sample characteristics stratified by change in eCRF are shown in
Characteristics of study population stratified by change in eCRF, relative to sex-, and age-defined median, from HUNT2 to HUNT3 (
Age at HUNT MRI, mean, SD | 60.3 ± 3.88 | 56.9 ± 3.34 | 60.8 ± 3.43 | 57.6 ± 4.15 |
Women, |
137 (51.7) | 59 (52.7) | 57 (51.8) | 137 (51.9) |
University/college, |
70 (26.4) | 36 (32.1) | 33 (30.0) | 110 (41.7) |
Smokers (current), |
67 (25.3) | 31 (27.7) | 29 (26.4) | 58 (22.0) |
Remained low | 217 (81.9) | 86 (76.8) | 92 (83.6) | 213 (80.7) |
Improved | 14 (5.3) | 12 (10.7) | 9 (8.2) | 23 (8.7) |
Worsened | 17 (6.4) | 7 (6.3) | 3 (2.7) | 18 (6.8) |
Remained high | 17 (6.4) | 7 (6.3) | 6 (5.5) | 10 (3.8) |
Remained low | 217 (81.9) | 92 (83.0) | 100 (90.9) | 235 (89.0) |
Improved | 11 (4.2) | 3 (2.7) | 6 (5.5) | 12 (4.5) |
Worsened | 25 (9.4) | 9 (8.0) | 2 (1.8) | 14 (5.3) |
Remained high | 12 (4.5) | 7 (6.3) | 2 (1.8) | 3 (1.1) |
HADS-A HUNT2, mean, SD | 3.93 ± 3.06 | 4.35 ± 3.83 | 3.53 ± 2.93 | 3.81 ± 2.99 |
ΔHADS-A |
−0.15 ± 2.99 | −0.55 ± 3.41 | −0.13 ± 2.52 | −0.34 ± 2.92 |
HADS-D HUNT2, mean, SD | 3.56 ± 2.94 | 3.32 ± 3.26 | 2.92 ± 2.69 | 2.67 ± 2.64 |
ΔHADS-D |
0.03 ± 2.90 | −0.11 ± 3.01 | 0.01 ± 2.19 | 0.08 ± 2.56 |
eCRF HUNT2, mean, SD | 38.5 ± 5.23 | 43.9 ± 4.76 | 40.5 ± 4.66 | 45.3 ± 5.41 |
ΔeCRF |
−6.81 ± 2.82 | −9.97 ± 2.25 | −3.13 ± 2.19 | −5.76 ± 2.35 |
Standardized beta coefficients (β) and 95% confidence intervals (CI) for the associations of changes in eCRF and HADS from HUNT2 to HUNT3 on BPF, hippocampal, and cortical volume measured at HUNT3 (
Remained low | 265 | Ref. | 0.22 | Ref. | 0.40 | Ref. | 0.77 |
Decreased | 112 | 0.01 (−0.07, 0.08) | 0.04 (−0.02, 0.11) | −0.003 (−0.04, 0.04) | |||
Increased | 110 | 0.02 (−0.01, 0.06) | |||||
Remained high | 264 | 0.05 (−0.02, 0.12) | |||||
Remained low | 608 | Ref. | 0.21 | Ref. | 0.40 | Ref. | 0.77 |
Improved | 58 | 0.01 (−0.05, 0.08) | −0.01 (−0.06, 0.05) | 0.001 (−0.03, 0.04) | |||
Worsened | 45 | – |
−0.06 (−0.11, 0.001) | – |
|||
Remained high | 40 | −0.01 (−0.08, 0.05) | 0.03 (−0.03, 0.09) | −0.01 (−0.04, 0.03) | |||
Remained low | 645 | Ref. | 0.21 | Ref. | 0.39 | Ref. | 0.77 |
Improved | 32 | 0.02 (−0.05, 0.08) | −0.01 (−0.07, 0.05) | −0.01 (−0.04, 0.03) | |||
Worsened | 50 | −0.05 (−0.11, 0.02) | −0.03 (−0.08, 0.03) | −0.03 (−0.07, 0.01) | |||
Remained high | 24 | −0.04 (−0.10, 0.03) | 0.01 (−0.05, 0.07) | −0.002 (−0.04, 0.03) | |||
ΔeCRF |
751 | 0.24 | 0.40 | 0.78 | |||
ΔHADS-A |
751 | – |
0.21 | −0.05 (−0.12, 0.01) | 0.40 | – |
0.77 |
ΔHADS-D |
751 | −0.07 (−0.15, 0.001) | 0.21 | −0.01 (−0.08, 0.05) | 0.39 | −0.03 (−0.07, 0.01) | 0.77 |
Standardized beta coefficients (β) and 95% confidence intervals (CI) for the association of ΔeCRF from HUNT2 to HUNT3 with BPF, hippocampal, and cortical volume measured at HUNT3, stratified by change in HADS (
Remained low | 608 | 0.24 | 0.38 | 0.78 | |||
Improved | 58 | 0.25 (−0.01, 0.51) | 0.26 | 0.09 (−0.13, 0.30) | 0.61 | 0.08 (−0.07, 0.22) | 0.79 |
Worsened | 45 | 0.07 (−0.17, 0.32) | 0.38 | 0.14 (−0.12, 0.40) | 0.44 | 0.82 | |
Remained high | 40 | 0.12 (−0.14, 0.37) | 0.24 | 0.10 (−0.16, 0.36) | 0.30 | 0.02 (−0.14, 0.18) | 0.69 |
Remained low | 645 | 0.23 | 0.39 | 0.77 | |||
Improved | 32 | 0.49 | 0.09 (−0.34, 0.51) | 0.35 | 0.15 (−0.02, 0.31) | 0.83 | |
Worsened | 50 | −0.03 (−0.27, 0.21) | 0.24 | 0.16 (−0.09, 0.41) | 0.53 | 0.11 (−0.02, 0.23) | 0.85 |
Remained high | 24 | 0.26 (−0.26, 0.78) | 0.42 | 0.29 (−0.17, 0.76) | 0.39 | −0.14 (−0.38, 0.09) | 0.81 |
Participants in the “increased” eCRF group and in the “remained high” eCRF group had larger BPF; β = 0.09 (95% CI 0.02, 0.16) and β = 0.15 (95% CI 0.07, 0.22), respectively, compared to participants in the “remained low” eCRF group. In addition, each ml/kg/min increase in ΔeCRF corresponded to a larger BPF, β = 0.16 (95% CI 0.10, 0.23).
Participants in the “worsened” HADS-A group had smaller BPF, β = −0.09 (95% CI −0.15, −0.02), compared to participants in the “remained low” HADS-A group. Further, each unit increase in ΔHADS-A was associated with a smaller BPF, β = −0.07 (95% CI −0.15, −0.002). ΔHADS-D was associated with smaller BPF, although this result did not reach statistical significance, β = −0.07 (95% CI −0.15, 0.001) (
Participants in the “increased” eCRF group had a larger hippocampal volume, β = 0.09 (95% CI 0.03, 0.16), compared to participants in the “remained low” eCRF group. Furthermore, each ml/kg/min increase in ΔeCRF was associated with a larger hippocampal volume, β = 0.09 (95% CI 0.03, 0.15).
Neither change in HADS-A nor HADS-D was significantly associated with hippocampal volume (
Participants in the “remained high” eCRF group had larger cortical volume, β = 0.05 (95% CI 0.01, 0.09), compared to those in the “remained low” eCRF group. In addition, each ml/kg/min increase in ΔeCRF corresponded to a larger cortical volume, β = 0.05 (95% CI 0.02, 0.09).
Participants in the “worsened” HADS-A group had smaller cortical volume compared to those in the “remained low” HADS-A group, β = −0.05 (95% CI −0.08, −0.01). Further, each unit increase in ΔHADS-A was associated with smaller cortical volume, β = −0.04 (95% CI −0.08, −0.003). Change in HADS-D was not significantly associated with cortical volume (
In analyses stratified by categorical HADS change, each ml/kg/min increase in ΔeCRF was associated with larger BPF (β = 0.17, 95% CI 0.09, 0.24), hippocampal (β = 0.08, 95% CI 0.01, 0.14) and cortical volume (β = 0.04, 95% CI 0.004, 0.08) among participants in the “remained low” HADS-A group. In the “worsened” HADS-A group, each ml/kg/min increase in ΔeCRF was associated with larger cortical volume, β = 0.13 (95% CI 0.001, 0.27). In the “remained low” HADS-D group, each ml/kg/min increase in ΔeCRF was associated with larger BPF (β = 0.17, 95% CI 0.10, 0.24), hippocampal (β = 0.08, 95% CI 0.02, 0.14), and cortical volume (β = 0.05, 95% CI 0.01, 0.09). In addition, each ml/kg/min increase in ΔeCRF was associated with larger BPF in the “improved” HADS-D group, β = 0.28 (95% CI 0.02, 0.53) (
Analyses assessing independent changes in eCRF, HADS-A, and HADS-D did not alter the associations, although the association between ΔHADS-A and BPF and ΔHADS-A and cortical volume was attenuated and was no longer statistically significant after adding ΔHADS-D, HADS-D at HUNT2, ΔeCRF, and eCRF at HUNT2 to the model (
In our study of 751 adults from the general population, we found that increasing or maintaining a high eCRF during middle-age was associated with larger BPF, hippocampal and total cortical volume. Worsening of anxiety symptoms was associated with smaller BPF and total cortical volume. In the stratified analyses, increasing eCRF was associated with larger brain volumes among individuals whose anxiety and depressive symptoms remained low, among individuals with worsening anxiety symptoms, and among those with improving depressive symptoms.
The increased brain volumes observed among individuals whose eCRF increased or remained high is in accordance with previous studies showing larger whole brain (Zhu et al.,
Earlier studies investigating gray matter volume in anxiety disorders have found smaller volumes in the hippocampus, midbrain, thalamus, insula, and superior temporal gyrus among patients with general anxiety disorder (Moon et al.,
Surprisingly, we did not observe a statistically significant association between changes in depressive symptoms and brain volumes, although we observed a similar reduction in BPF associated with ΔHADS-D as observed for ΔHADS-A (see
To our knowledge, no previous study has investigated the joint associations of long-term changes in eCRF and symptoms of anxiety and depression on brain volumes. The results from stratified analyses showed that increased eCRF was associated with larger cortical volume among participants whose symptoms of anxiety worsened and with larger BPF among participants whose symptoms of depression had improved. With few exceptions, eCRF was positively associated with larger brain volumes across all strata of change in HADS-A and HADS-D, even though a number of these associations did not reach statistical significance. Given that anxiety and depressive symptoms are common among older adults (Reynolds et al.,
The present study has several strengths. First, the study included a large, validated, population-based sample with a relatively narrow age range and an acceptable participation rate of 71.1% for the age group 60–69 at HUNT3 (Krokstad et al.,
The main limitation of our study is the lack of longitudinal brain MRI data, making causal inferences about the observed associations between changes in eCRF, symptoms of anxiety and depression, and change in brain volumes impossible. However, there is evidence indicating that both anxiety (Mah et al.,
In conclusion, our study demonstrated that increasing or maintaining high eCRF during midlife was associated with larger BPF, and hippocampal and cortical volume in a sample of middle-aged adults drawn from the general population. Worsening of anxiety symptoms was associated with smaller BPF and cortical volume. Importantly, increased eCRF appeared to be especially beneficial for cortical volume among individuals with worsening anxiety symptoms. In sum, our findings underline the importance of physical activity promotion, and anxiety prevention, as a means of promoting healthy brain aging in the general population. Health care professionals in primary clinical practice should promote physical activity and emphasize treating anxiety symptoms in order to maintain brain health among middle-aged individuals.
The data analyzed in this study was obtained from the HUNT Research Center. Instructions and requirements for data access are available on the following website
EZ, CP, ØS, GS, AH, and LE all contributed to the conceptualization and design of the study, drafting and revising of the manuscript prior to submission and during revision.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health.
The Supplementary Material for this article can be found online at:
brain parenchymal fraction
cardiorespiratory fitness
estimated cardiorespiratory fitness
Hospital Anxiety and Depression Scale
Hospital Anxiety and Depression Scale anxiety subscale
Hospital Anxiety and Depression Scale depression subscale
Nord-Trøndelag Health Study
intracranial volume
resting heart rate
waist circumference.