BACKGROUND AND OBJECTIVES: Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals. METHODS: The contribution of amyloid and tau pathology was assessed through CSF levels of the Aβ42/40 ratio and phosphorylated tau (p-tau). CSF Aβ38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis as variables of interest. RESULTS: We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of Aβ38 and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The Aβ42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE ε4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T201 = -1.55; p = 0.123). DISCUSSION: In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.

From the Division of Clinical Geriatrics Centre for Neuroimaging Sciences Institute of Psychiatry Psychology and Neuroscience King's College London UK

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Mesulam M-M. Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer's disease. J Comp Neurol. 2013;521(18):4124-4144. doi.wiley.com/10.1002/cne.23415. PubMed DOI PMC

Herdick M, Dyrba M, Fritz H-CJ, et al. . Multimodal MRI analysis of basal forebrain structure and function across the Alzheimer's disease spectrum. Neuroimage Clin. 2020;28:102495. 10.1016/j.nicl.2020.102495. PubMed DOI PMC

Fritz HCJ, Ray N, Dyrba M, Sorg C, Teipel S, Grothe MJ. The corticotopic organization of the human basal forebrain as revealed by regionally selective functional connectivity profiles. Hum Brain Mapp. 2019;40(3):868-878. PubMed PMC

Nemy M, Cedres N, Grothe MJ, et al. . Cholinergic white matter pathways make a stronger contribution to attention and memory in normal aging than cerebrovascular health and nucleus basalis of Meynert. Neuroimage. 2020;211:116607. PubMed

Teipel SJ, Meindl T, Grinberg L, et al. . The cholinergic system in mild cognitive impairment and Alzheimer's disease: an in vivo MRI and DTI study. Hum Brain Mapp. 2011;32(9):1349-1362. PubMed PMC

Cedres N, Ferreira D, Machado A, et al. . Predicting Fazekas scores from automatic segmentations of white matter signal abnormalities. Aging (Albany NY). 2020;12(1):894-901. aging-us.com/article/102662/text. PubMed PMC

Rydberg Sterner T, Ahlner F, Blennow K, et al. . The Gothenburg H70 Birth cohort study 2014-16: design, methods and study population. Eur J Epidemiol. 2019;34(2):191-209. link.springer.com/10.1007/s10654-018-0459-8. PubMed DOI PMC

Fischl B, Salat DH, Busa E, et al. . Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002;33(3):341-355. PubMed

Schmidt P, Gaser C, Arsic M, et al. . An automated tool for detection of FLAIR-hyperintense white-matter lesions in Multiple Sclerosis. Neuroimage. 2012;59(4):3774-3783. 10.1016/j.neuroimage.2011.11.032. PubMed DOI

Riphagen JM, Gronenschild EHBM, Salat DH, et al. . Shades of white: diffusion properties of T1- and FLAIR-defined white matter signal abnormalities differ in stages from cognitively normal to dementia. Neurobiol Aging. 2018;68:48-58. linkinghub.elsevier.com/retrieve/pii/S0197458018301180. PubMed

Olsson E, Klasson N, Berge J, et al. . White matter lesion assessment in patients with cognitive impairment and healthy controls: reliability comparisons between visual rating, a manual, and an automatic volumetrical MRI method–the gothenburg MCI study. J Aging Res. 2013;2013:198471. PubMed PMC

Muehlboeck J-S, Westman E, Simmons A. TheHiveDB image data management and analysis framework. Front Neuroinform. 2014;7:49-13. journal.frontiersin.org/article/10.3389/fninf.2013.00049/abstract. PubMed DOI PMC

Voevodskaya O. The effects of intracranial volume adjustment approaches on multiple regional MRI volumes in healthy aging and Alzheimer's disease. Front Aging Neurosci. 2014;6:1-14. PubMed PMC

Avants BB, Epstein CL, Grossman M, Gee JC. Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal. 2008;12(1):26-41. ncbi.nlm.nih.gov/pmc/articles/PMC3624763/pdf/nihms412728.pdf. PubMed PMC

Avants BB, Yushkevich P, Pluta J, Minkoff D, Korczykowski M, Detre J, Gee JC. The optimal template effect in hippocampus studies of diseased populations. Neuroimage. 2010;49(3):2457-66. doi: 10.1016/j.neuroimage.2009.09.062. PubMed PMC

Smith S.M, Jenkinson M, Woolrich M.W, Beckmann CF, Behrens T.E.J, Johansen-Berg H, et al. . Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage. 2004;23(S1):208-19. PubMed

Dauguet J, Peled S, Berezovskii V, et al. . Comparison of fiber tracts derived from in-vivo DTI tractography with 3D histological neural tract tracer reconstruction on a macaque brain. Neuroimage. 2007;37(2):530-538. sciencedirect.com/science/article/pii/S105381190700328X. PubMed

Badji A, Pereira JB, Shams S, et al. . Cerebrospinal fluid biomarkers, brain structural and cognitive performances between normotensive and hypertensive controlled, uncontrolled and untreated 70-year-old adults. Front Aging Neurosci. 2021;13:777475. PubMed PMC

Rydén L, Sacuiu S, Wetterberg H, et al. . Atrial fibrillation, stroke, and silent cerebrovascular disease: a population-based MRI study. Neurology. 2021;97(16):E1608-E1619. PubMed PMC

Wardlaw JM, Smith EE, Biessels GJ, et al. , Standards for ReportIng Vascular Changes on Neuroimaging STRIVE v1. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12(8):822-838. ncbi.nlm.nih.gov/pubmed/23867200. PubMed PMC

Hansson O, Lehmann S, Otto M, Zetterberg H, Lewczuk P. Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer's Disease. Alzheimers Res Ther. 2019;11:1-15. PubMed PMC

Kern S, Zetterberg H, Zettergren A, et al. . The prevalence of preclinical Alzheimer's disease in a population study of 70-year-olds. Alzheimers Dement. 2017;13:P848. linkinghub.elsevier.com/retrieve/pii/S1552526017314279.

Wiltfang J, Esselmann H, Bibl M, et al. . Highly conserved and disease-specific patterns of carboxyterminally truncated Abeta peptides 1-37/38/39 in addition to 1-40/42 in Alzheimer's disease and in patients with chronic neuroinflammation. J Neurochem. 2002;81(3):481-496. PubMed

Reinert J, Martens H, Huettenrauch M, et al. . Aβ38 in the brains of patients with sporadic and familial Alzheimer's disease and transgenic mouse models. J Alzheimers Dis. 2014;39(4):871-881. PubMed

Heywood WE, Hallqvist J, Heslegrave AJ, et al. . CSF pro-orexin and amyloid-β38 expression in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging. 2018;72:171-176. 10.1016/j.neurobiolaging.2018.08.019. PubMed DOI PMC

Mulugeta E, Londos E, Ballard C, et al. . CSF amyloid β38 as a novel diagnostic marker for dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2011;82(2):160-164. PubMed

Van Steenoven I, Van Der Flier WM, Scheltens P, Teunissen CE, Lemstra AW. Amyloid-β peptides in cerebrospinal fluid of patients with dementia with Lewy bodies. Alzheimers Res Ther. 2019;11:8-10. PubMed PMC

R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2022. https://www.R-project.org/.

Breiman L. Bagging predictions. Mach Learn. 1996;24:123-140.

Breiman L Random forests. Mach Learn.2001;45(1):5-32.

Cedres N, Diaz-Galvan P, Diaz-Flores L, et al. . The interplay between gray matter and white matter neurodegeneration in subjective cognitive decline. Aging (Albany NY). 2021;13(16):19963-19977. PubMed PMC

Liaw AL, Wiener M. Classification and regression by randomForest. R News 2. 2003;3:18-22.

Hothorn T, Hornik K, Strobl C, Zeileis A. party: A Laboratory for Recursive Partytioning. R Package Version 09-0. 2015:37. http//CRAN R-project orgparty.r-forge.r-project.org/.

Dumas JA, Kutz AM, Mcdonald BC, et al. . Aged women with cognitive complaints. Neurobiol Aging. 2014;34:1145-1147. PubMed PMC

Contestabile A. The history of the cholinergic hypothesis. Behav Brain Res. 2011;221(2):334-340. 10.1016/j.bbr.2009.12.044. PubMed DOI

Benedictus MR, Van Harten AC, Leeuwis AE, et al. . White matter hyperintensities relate to clinical progression in subjective cognitive decline. Stroke. 2015;46(9):2661-2664. PubMed

Lindberg O, Kern S, Skoog J, et al. . Effects of amyloid pathology and the APOE ε4 allele on the association between cerebrospinal fluid Aβ38 and Aβ40 and brain morphology in cognitively normal 70-years-old. Neurobiol Aging. 2021;101:1-12. PubMed

Bibl M, Mollenhauer B, Lewczuk P, et al. . Cerebrospinal fluid tau, p-tau 181 and amyloid-β38/40/42 in frontotemporal dementias and primary progressive aphasias, Dement Geriatr Cogn Disord. 2011;31:37-44. karger.com/DOI/10.1159/000322370. PubMed DOI

Hilal S, Akoudad S, Van Duijn CM, et al. . Plasma amyloid-β levels, cerebral small vessel disease, and cognition: The Rotterdam study. J Alzheimers Dis. 2017;60(3):977-987. PubMed

Cullen N, Janelidze S, Palmqvist S, Stomrud E, Mattsson-Carlgren N, Hansson O, Alzheimer's Disease Neuroimaging Initiative. Association of CSF Aβ38 levels with risk of Alzheimer disease–related decline. Neurology. 2022;98(9):e958-e967. doi: 10.1212/WNL.0000000000013228. PubMed DOI PMC

Hadland KA, Rushworth MFS, Gaffan D, Passingham RE. The effect of cingulate lesions on social behaviour and emotion. Neuropsychologia. 2003;41(8):919-931. PubMed

de Leeuw FE, de Groot JC, Achten E, et al. . Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry. 2001;70(1):9-14. ncbi.nlm.nih.gov/pubmed/11118237. PubMed PMC

Bohnen NI, Müller MLTM, Kuwabara H, Constantine GM, Studenski SA. Age-associated leukoaraiosis and cortical cholinergic deafferentation. Neurology. 2009;72(16):1411-1416. PubMed PMC

Miller A-M, Balasa M, Blennow K, et al. . Current approaches and clinician attitudes to the use of cerebrospinal fluid biomarkers in diagnostic evaluation of dementia in europe. J Alzheimers Dis. 2017;60(1):201-210. PubMed

McAleese KE, Firbank M, Dey M, et al. . Cortical tau load is associated with white matter hyperintensities. Acta Neuropathologica Commun. 2015;3:60. 10.1186/s40478-015-0240-0. PubMed DOI PMC

Kim SH, Kang HS, Kim HJ, et al. . The effect of ischemic cholinergic damage on cognition in patients with subcortical vascular cognitive impairment. J Geriatr Psychiatry Neurol. 2012;25(2):122-127. 10.1177/0891988712445089. PubMed DOI

Behl P, Bocti C, Swartz RH, et al. . Strategic subcortical hyperintensities in cholinergic pathways and executive function decline in treated Alzheimer patients. Arch Neurol. 2007;64(2):266-272. PubMed

Cholinergic white matter pathways along the Alzheimer's disease continuum