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Short telomeres in depression and the general population are associated with a hypocortisolemic state
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
Linköping University, Department of Behavioral Sciences and Learning.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2012 (English)In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 71, no 4, 294-300 p.Article in journal (Refereed) Published
Abstract [en]

Background: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in stress regulation, and leukocyte telomere length (TL) has been suggested to represent a cumulative measure of stress. Depression is intimately related with stress and frequently exhibits a dysregulated HPA axis. We aimed to study the relationships between TL and biological and psychological facets of stress in recurrent major depressive disorder and controls.

Methods: Leukocyte TL was measured in 91 subjects with recurrent major depressive disorder and 451 control subjects. Stress was assessed from both a biological perspective, by assessing HPA axis function with a weight-adjusted very-low-dose dexamethasone suppression test (DST), and a psychological perspective, with self-report questionnaires.

Results: TL was shorter among patients compared with control subjects (277 base pairs, p = .001). Overall, short TL was associated with a hypocortisolemic state (low post-DST cortisol and high percentage of cortisol reduction after the DST) among both patients and control subjects but more pronounced among patients. This state, which was overrepresented among patients, was characterized by high familial loading of affective disorders among patients (p = .001) and high C-reactive protein levels among control subjects (p = .040). TL was also inversely associated with stress measured with the Perceived Stress Questionnaire (rs = −.258, p = .003).

Conclusions: Short TL is associated with depression and hypocortisolism. Because hypocortisolism has been shown to develop from chronic stress exposure, our findings corroborate the concept of TL as a cumulative measure of stress and provide novel insights into the detrimental role of stress in depressive illness and the general population.

Place, publisher, year, edition, pages
New York: Plenum , 2012. Vol. 71, no 4, 294-300 p.
Keyword [en]
Cortisol, hypocortisolism, hypothalamic-pituitary-adrenal axis, major depressive disorder, stress, telomere length
National Category
Psychiatry
Identifiers
URN: urn:nbn:se:umu:diva-49384DOI: 10.1016/j.biopsych.2011.09.015ISI: 000299314800007PubMedID: 22055018OAI: oai:DiVA.org:umu-49384DiVA: diva2:455500
Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Telomeres and the brain: an investigation into the relationships of leukocyte telomere length with functional and structural attributes of the brain
Open this publication in new window or tab >>Telomeres and the brain: an investigation into the relationships of leukocyte telomere length with functional and structural attributes of the brain
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Telomerer och hjärnan : en undersökning av sambanden mellan leukocyt-telomerlängd och funktionella och strukturella egenskaper hos hjärnan
Abstract [en]

Telomeres are the outermost parts of linear chromosomes. They consist of tandemly repeated non-coding short nucleotide sequences (TTAGGG in all vertebrates), in humans spanning over the last 2 to 15 kilobase pairs of the chromosome. Due to the end-replication problem, telomeres shorten with each cellular division. A critically short telomere will trigger the cell to enter a state of cellular senescence or to apoptose. The rate of telomere shortening can be accelerated by factors such as oxidative stress and inflammation. Taken together, this contributed to making telomere length a candidate biomarker of health and aging. Studies have shown that leukocyte telomere length progressively shortens with age, and that it independent of age is associated with age-related morbidity, lifestyle factors, and mortality. This thesis was aimed at exploring the relationships of leukocyte telomere length with various functional and structural attributes of the brain.

In Paper I, telomere length was shown to be longer among non-demented carriers of the apolipoprotein E (APOE) ε4 allele, a well-established risk factor for Alzheimer’s disease. However, the rate of telomere shortening was greater among the ε4 carriers, possibly due to the higher levels of oxidative stress and inflammation associated with this allele. Furthermore, performance on episodic memory tests was inversely related to telomere length among ε4 carriers. The results may contribute to a better understanding of the pathophysiology related to the APOE ε4 allele.

The volume of the hippocampus, a structure in the brain critical for episodic memory function, was in Paper II found to be inversely related to telomere length among non-demented APOE ε3/ε3 carriers. No correlation between hippocampal volume and telomere length was discernible among ε4 carriers, but they fit the pattern exhibited by the ε3/ε3 carriers as they tended to have smaller hippocampi and longer telomere length compared with the ε3/ε3 carriers. The results are possibly explained by a low proliferative activity among subjects with smaller hippocampi, which might also explain the inverse association between telomere length and episodic memory performance in Paper I.

In Paper III, we describe results corroborating earlier findings of shorter telomere length among individuals suffering from depression. Moreover, we found that the shorter telomere length among the patients to a large extent could be linked to a hypocortisolemic state; a state which has been associated with chronic stress. The findings corroborate the link between telomere length and stress, and underline the role of stress in depressive illness.

Two prominent manifestations of the aging brain are atrophy and white matter hyperintensities. In Paper IV, we report that white matter hyperintensities and cerebral subcortical atrophy were associated with shorter telomere length in aged non-demented individuals. Cortical atrophy was not associated with telomere length. Inflammation may be the underlying cause of the associations, as it is linked to telomere attrition, subcortical atrophy, and white matter hyperintensities.

Taken together, these results show that leukocyte telomere length has the potential of being used as a biomarker for structural and functional attributes of the brain. Furthermore, the findings can provide new insights into mechanisms of disease and aging of the brain

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2011. 72 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1469
Keyword
APOE, aging, atrophy, brain, cognition, cortisol, depression, hippocampus, HPA axis, MRI, stress, telomere length, white matter hyper-intensities.
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-50634 (URN)978-91-7459-338-9 (ISBN)
Public defence
2012-01-20, E04, byggnad 6E, Biomedicinhuset, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-12-23 Created: 2011-12-16 Last updated: 2012-07-09Bibliographically approved
2. Hypocortisolism in recurrent affective disorders
Open this publication in new window or tab >>Hypocortisolism in recurrent affective disorders
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bipolar disorders and recurrent depressions are two common psychiatric disorders with a life time prevalence of approximately 1% and 8%, respectively. Despite treatment these patients suffer from affective symptoms up to 50% of the time, resulting in lower well-being. The average life length is also reduced with 10-15 years, mainly attributable to suicide and cardiovascular disease. Increased stress is one of many factors that have been shown to be linked to an increased risk for developing affective disorders and some comorbid somatic conditions such as metabolic disturbances and cardiovascular disease. An increased stress level is known to cause hyperactivity of the hypothalamic-pituitary-adrenal-axis (HPA-axis) with increased cortisol secretion. Hyperactivity of the HPA-axis (or hypercortisolism) is one of the most replicated neurobiological finding in depression. In other stress related disorders it has however been shown that prolonged stress over long periods of time can lead to a state of low HPA-axis activity, hypocortisolism. Since persons with recurrent affective disorders such as bipolar disorder and recurrent depression are exposed to a high degree of recurrent and chronic stress it could be expected that in addition to hypercortisolism, a state of hypocortisolism could also develop in these disorders, potentially exerting an influence upon the psychological and somatic wellbeing among these patients.

The major aim of this thesis was to evaluate whether hypocortisolism is related to relevant psychiatric and somatic phenotypes in recurrent affective disorders.

In bipolar disorder, individuals with hypocortisolism exhibited a higher degree of depression and low quality of life compared to patients with normal HPA-axis activity. In recurrent depression, individuals with hypocortisolism exhibited shorter leukocyte telomere length than patients with normal or high HPA-axis activity, which is an indication of an accelerated aging process. In a sample of both bipolar and recurrent depression patients, hypocortisolism was associated with an increased proportion of obesity, dyslipidemia and metabolic syndrome compared with patients with normal or high HPA-axis activity. Patients with recurrent depression showed a higher occurrence of hypocortisolism than the control sample representative of the general population. Patients with bipolar disorder showed a similar occurrence of hypocortisolism as the control sample. Among bipolar disorder patients with a low degree of lifetime with lithium prophylaxis, there was an inverse correlation between age and HPA-axis activity. In contrast, among patients with a higher degree of lifetime with lithium prophylaxis as well as among the controls, there was no correlation between age and HPA-axis activity. Accordingly, hypocortisolism was most common among older patients with a low degree of lifetime with lithium prophylaxis. In conclusion, hypocortisolism in both recurrent depression and bipolar disorder was associated with multiple clinically-relevant phenotypes. Additionally it was shown for bipolar disorder patients that increasing age was a risk factor for hypocortisolism and that prophylactic lithium treatment was a protective factor. It is argued that the protective effect of lithium towards the HPA-axis is attributable to its mood-stabilizing effect, which in turn reduces the chronic stress level. These results provide new insight into the role of hypocortisolism and chronic stress in recurrent affective disorders warranting further studies and hopefully providing clues to improved treatment strategies.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2015. 55 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1766
Keyword
Affective disorders, Bipolar disorder, Cortisol, Depression, HPA-axis, Hypercortisolism, Hypocortisolism, Lithium, Metabolic syndrome, Obesity, Quality of life, Recurrent depression, Stress, Telomeres
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-112824 (URN)978-91-7601-383-0 (ISBN)
Public defence
2016-01-22, Föreläsningssal A, Psykiatriska kliniken, Byggnad 23, Plan 0, Norrlands universitetssjukhus (NUS), Umeå, 13:00 (Swedish)
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Supervisors
Available from: 2015-12-18 Created: 2015-12-15 Last updated: 2016-01-08Bibliographically approved

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