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Telomeres and the brain: an investigation into the relationships of leukocyte telomere length with functional and structural attributes of the brain
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Telomerer och hjärnan : en undersökning av sambanden mellan leukocyt-telomerlängd och funktionella och strukturella egenskaper hos hjärnan (Swedish)
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 [en]
APOE, aging, atrophy, brain, cognition, cortisol, depression, hippocampus, HPA axis, MRI, stress, telomere length, white matter hyper-intensities.
National Category
Psychiatry
Identifiers
URN: urn:nbn:se:umu:diva-50634ISBN: 978-91-7459-338-9 (print)OAI: oai:DiVA.org:umu-50634DiVA: diva2:466502
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
List of papers
1. APOE ε4 is associated with longer telomeres, and longer telomeres among ε4 carriers predicts worse episodic memory
Open this publication in new window or tab >>APOE ε4 is associated with longer telomeres, and longer telomeres among ε4 carriers predicts worse episodic memory
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2012 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 2, 335-344 p.Article in journal (Refereed) Published
Abstract [en]

Both leukocyte telomere length and the apolipoprotein epsilon4 allele have been associated with mortality, cardiovascular disease, cognition, and dementia. The authors investigated whether leukocyte telomere length was associated with APOE genotype or cognitive abilities in the context of APOE genotype. The setting for this cross-sectional study was 427 nondemented individuals aged 41-81 yr. The authors found that epsilon4 carriers overall exhibited significantly longer telomeres compared with non-carriers (difference of 268 bp, p = 0.001). This difference was greatest at the lower limit of the age span and nonsignificant at the upper limit, which translated into a significantly higher telomere attrition rate (p = 0.049) among epsilon4 carriers (37 bp/years) compared with non-carriers (21 bp/year). Further, longer telomeres among epsilon4 carriers significantly predicted worse performance on episodic memory tasks. No significant associations were found on tasks tapping semantic and visuospatial ability, or among epsilon3/epsilon3 carriers. In conclusion, APOE epsilon4 carriers had longer telomeres compared with non-carriers, but higher rate of attrition. Among them, longer telomeres predicted worse performance on episodic memory tasks. These observations suggest that the epsilon4 allele is associated with abnormal cell turnover of functional and possibly clinical significance.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
APOE, Cognition, Telomere length
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-33698 (URN)10.1016/j.neurobiolaging.2010.03.004 (DOI)000298171800012 ()20395015 (PubMedID)
External cooperation:
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2017-12-12Bibliographically approved
2. Longer leukocyte telomere length is associated with smaller hippocampal volume among non-demented APOE ε3/ε3 subjects
Open this publication in new window or tab >>Longer leukocyte telomere length is associated with smaller hippocampal volume among non-demented APOE ε3/ε3 subjects
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, e34292- p.Article in journal (Refereed) Published
Abstract [en]

Telomere length shortens with cellular division, and leukocyte telomere length is used as a marker for systemic telomere length. The hippocampus hosts adult neurogenesis and is an important structure for episodic memory, and carriers of the apolipoprotein E ε4 allele exhibit higher hippocampal atrophy rates and differing telomere dynamics compared with non-carriers. The authors investigated whether leukocyte telomere length was associated with hippocampal volume in 57 cognitively intact subjects (29 ε3/ε3 carriers; 28 ε4 carriers) aged 49-79 yr. Leukocyte telomere length correlated inversely with left (r(s) = -0.465; p = 0.011), right (r(s) = -0.414; p = 0.025), and total hippocampus volume (r(s) = -0.519; p = 0.004) among APOE ε3/ε3 carriers, but not among ε4 carriers. However, the ε4 carriers fit with the general correlation pattern exhibited by the ε3/ε3 carriers, as ε4 carriers on average had longer telomeres and smaller hippocampi compared with ε3/ε3 carriers. The relationship observed can be interpreted as long telomeres representing a history of relatively low cellular proliferation, reflected in smaller hippocampal volumes. The results support the potential of leukocyte telomere length being used as a biomarker for tapping functional and structural processes of the aging brain.

Place, publisher, year, edition, pages
Public Library of Science, 2012
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-54207 (URN)10.1371/journal.pone.0034292 (DOI)000305297500024 ()22506016 (PubMedID)
Available from: 2012-04-19 Created: 2012-04-19 Last updated: 2017-12-07Bibliographically approved
3. Short telomeres in depression and the general population are associated with a hypocortisolemic state
Open this publication in new window or tab >>Short telomeres in depression and the general population are associated with a hypocortisolemic state
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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
Keyword
Cortisol, hypocortisolism, hypothalamic-pituitary-adrenal axis, major depressive disorder, stress, telomere length
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-49384 (URN)10.1016/j.biopsych.2011.09.015 (DOI)000299314800007 ()22055018 (PubMedID)
Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2017-12-08Bibliographically approved
4. Shorter telomere length is linked to brain atrophy and white matter hyperintensities
Open this publication in new window or tab >>Shorter telomere length is linked to brain atrophy and white matter hyperintensities
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2014 (English)In: Age and Ageing, ISSN 0002-0729, E-ISSN 1468-2834, Vol. 43, no 2, 212-217 p.Article in journal (Refereed) Published
Abstract [en]

Background: leukocyte telomere length (TL) is considered a marker of biological aging. Several studies have investigated the link between leukocyte TL and aging-associated functional attributes of the brain, but no prior study has investigated whether TL can be linked to brain atrophy and white matter hyperintensities (WMHs); two prominent structural manifestations of brain aging. Methods: we investigated whether leukocyte TL was related to brain atrophy and WMHs in a sample of 102 non-demented individuals aged 64-75 years. Results: shorter TL was related to greater degree of subcortical atrophy (beta = -0.217, P = 0.034), but not to cortical atrophy. Furthermore, TL was 371 bp shorter (P = 0.041) in participants exhibiting subcortical WMHs, and 552 bp shorter (P = 0.009) in older participants exhibiting periventricular WMHs. Conclusion: this study provides the first evidence of leukocyte TL being associated with cerebral subcortical atrophy and WMHs, lending further support to the concept of TL as a marker of biological aging, and in particular that of the aging brain.

Keyword
brain atrophy, older people, telomere length, white matter hyperintensities
National Category
Psychiatry Geriatrics
Identifiers
urn:nbn:se:umu:diva-50629 (URN)10.1093/ageing/aft172 (DOI)000332028600012 ()24231584 (PubMedID)
Note

Originally published in manuscript form with title The relationship of leukocyte telomere length with brain atrophy and white matter hyperintensities.

Available from: 2011-12-16 Created: 2011-12-16 Last updated: 2017-12-08Bibliographically approved

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