The incidence of Alzheimer’s disease (AD) strongly relates to advanced age and progressive deposition of cerebral amyloid-beta (Aβ), hyperphosphorylated tau, and iron. The purpose of this study was to investigate the relationship between cerebral dynamic functional connectivity and variability of long-term cognitive performance in healthy, elderly subjects, allowing for local pathology and genetic risk.
Thirty seven participants (mean (SD) age 74 (6.0) years, Mini-Mental State Examination 29.0 (1.2)) were dichotomized based on repeated neuropsychological test performance within 2 years. Cerebral Aβ was measured by 11C Pittsburgh Compound-B positron emission tomography, and iron by quantitative susceptibility mapping magnetic resonance imaging (MRI) at an ultra-high field strength of 7 Tesla (7T). Dynamic functional connectivity patterns were investigated by resting-state functional MRI at 7T and tested for interactive effects with genetic AD risk (apolipoprotein E (ApoE)-ε4 carrier status).
A relationship between low episodic memory and a lower expression of anterior-posterior connectivity was seen (F(9,27) = 3.23, p < 0.008), moderated by ApoE-ε4 (F(9,27) = 2.22, p < 0.005). Inherent node-strength was related to local iron (F(5,30) = 13.2; p < 0.022).
Our data indicate that altered dynamic anterior-posterior brain connectivity is a characteristic of low memory performance in the subclinical range and genetic risk for AD in the elderly. As the observed altered brain network properties are associated with increased local iron, our findings may reflect secondary neuronal changes due to pathologic processes including oxidative stress.
Alzheimer A. About a peculiar disease of the cortex. Gen J Psychiatry Psychiatr Leg Med. 1907;64(1-2):146–8.
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280–92. CrossRefPubMedPubMedCentral
van Bergen JMG, Hua J, Unschuld PG, et al. Quantitative susceptibility mapping suggests altered brain iron in premanifest Huntington’s disease. Am J Neuroradiol. 2015. In press. doi: 10.3174/ajnr.A4617.
Donahue MJ, Hoogduin H, Smith SM, et al. Spontaneous blood oxygenation level-dependent fMRI signal is modulated by behavioral state and correlates with evoked response in sensorimotor cortex: a 7.0-T fMRI study. Hum Brain Mapp. 2011;33:511–22.
Donahue MJ, Hoogduin H, van Zijl P, Jezzard P, Luijten PR, Hendrikse J. Blood oxygenation level-dependent (BOLD) total and extravascular signal changes and dR2* in human visual cortex at 1.5, 3.0 and 7.0 T. NMR Biomed. 2010;23:1–11. CrossRef
Elman JA, Madison CM, Baker SL, et al. Effects of beta-amyloid on resting state functional connectivity within and between networks reflect known patterns of regional vulnerability. Cereb Cortex. 2016;26(2):695–707. PubMed
Gietl AF, Warnock G, Riese F, et al. Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner. Neurobiol Aging. 2015;36:1619–28
World_Medical_Association. Declaration of Helsinki. Law Med Health Care. 1991;19(3–4):264–5.
Härting C, Markowitsch HJ, Neufeld H, Calabrese P, Diesinger K, Kessler J. Wechsler Memory Test—Revised version (WMS-R). Bern: Huber; 2000.
Helmstaedter C, Durwen HF. The Verbal Learning and Retention Test. A useful and differentiated tool in evaluating verbal memory performance. Schweiz Arch Neurol Psychiatr. 1990;141(1):21–30. PubMed
Nicholas LE, Brookshire RH, MacLennan DL, Schumacher JG, Porrazzo SA. The Boston Naming Test: revised administration and scoring procedures and normative information for non-brain-damaged adults. Clinical Aphasiology. 1988;18:103–15.
Thalmann B, Monsch AU, Bernasconi F, et al. CERAD—Consortium to Establish a Registry for Alzheimer’s Disease Assessment Battery—deutsche Fassung. Basel: Geriatrische Universitätsklinik; 1997.
Sporns O. Networks of the brain. Cambridge: MIT Press; 2011. p. 9–17.
Holm S. A simple sequentially rejective Bonferroni test procedure. Scand J Stat. 1979;6:65–70.
Storey JD. A direct approach to false discovery rates. J R Statist Soc B. 2002;64(3):479–98. CrossRef
Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Mahwah: Lawrence Erlbaum Associates; 1988.
Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):270–9. CrossRefPubMedPubMedCentral
Altamura S, Muckenthaler MU. Iron toxicity in diseases of aging: Alzheimer’s disease, Parkinson’s disease and atherosclerosis. J Alzheimers Dis. 2009;16(4):879–95. PubMed
Ill-Raga G, Ramos-Fernandez E, Guix FX, et al. Amyloid-beta peptide fibrils induce nitro-oxidative stress in neuronal cells. J Alzheimers Dis. 2010;22(2):641–52. PubMed
Bush AI. The metal theory of Alzheimer’s disease. J Alzheimers Dis. 2013;33 Suppl 1:S277–81. PubMed
- Memory performance-related dynamic brain connectivity indicates pathological burden and genetic risk for Alzheimer’s disease
Frances C. Quevenco
Maria G. Preti
Jiri M. G. van Bergen
Simon J. Schreiner
Stefanie C. Steininger
Irene B. Meier
Adam M. Brickman
Sandra E. Leh
Anton F. Gietl
Roger M. Nitsch
Klaas P. Pruessmann
Peter C. M. van Zijl
Dimitri Van De Ville
Paul G. Unschuld
- BioMed Central