Top

Published in:

Open Access 21-02-2024 | Mild Neurocognitive Disorder | Original Communication

Effect of cerebral small vessel disease on the integrity of cholinergic system in mild cognitive impairment patients: a longitudinal study

Authors: Tiantian Qiu, Hui Hong, Qingze Zeng, Xiaopei Xu, Yanyan Wang, Lixin Zhu, Lige Zhang, Kaicheng Li, Shouping Dai, Xiaodong Li, Fei Xie, Yusong Zhang, Xiao Luo, for the Alzheimer’s Disease Neuroimaging Initiative

Published in: Journal of Neurology | Issue 5/2024

Abstract

We aimed to investigate the effect of cerebral small vessel disease (SVD) on cholinergic system integrity in mild cognitive impairment (MCI) patients. Nucleus basalis of Meynert (NBM) volume and cholinergic pathways integrity was evaluated at baseline, 1-, 2-, and 4-year follow-ups in 40 cognitively unimpaired (CU) participants, 29 MCI patients without SVD, and 23 MCI patients with SVD. We compared cholinergic markers among three groups and examined their associations with SVD burden in MCI patients. We used linear mixed models to assess longitudinal changes in cholinergic markers over time among groups. Mediation analysis was employed to investigate the mediating role of cholinergic system degeneration between SVD and cognitive impairment. Increased mean diffusivity (MD) in medial and lateral pathways was observed in MCI patients with SVD compared to those without SVD and CU participants. Both MCI groups showed decreased NBM volume compared to CU participants, while there was no significant difference between the two MCI groups. Longitudinally, compared to CU participants, MCI patients with SVD displayed a more rapid change in MD in both pathways, but not in NBM volume. Furthermore, SVD burden was associated with cholinergic pathway disruption and its faster rate of change in MCI patients. However, mediation analyses showed that cholinergic pathways did not mediate significant indirect effects of SVD burden on cognitive impairment. Our findings suggest that SVD could accelerate the degeneration of cholinergic pathways in MCI patients. However, they do not provide evidence to support that SVD could contribute to cognitive impairment through cholinergic system injury.

Available only for authorised users

Attems J, Jellinger KA (2014) The overlap between vascular disease and Alzheimer’s disease–lessons from pathology. BMC Med 12:206PubMedPubMedCentral

Lee MJ, Seo SW, Na DL, Kim C, Park JH, Kim GH, Kim CH, Noh Y, Cho H, Kim HJ et al (2014) Synergistic effects of ischemia and β-amyloid burden on cognitive decline in patients with subcortical vascular mild cognitive impairment. JAMA Psychiat 71:412–422

Bangen KJ, Thomas KR, Weigand AJ, Sanchez DL, Delano-Wood L, Edmonds EC, Carmichael OT, Schwarz CG, Brickman AM, Bondi MW (2020) Pattern of regional white matter hyperintensity volume in mild cognitive impairment subtypes and associations with decline in daily functioning. Neurobiol Aging 86:134–142PubMed

Garnier-Crussard A, Bougacha S, Wirth M, Dautricourt S, Sherif S, Landeau B, Gonneaud J, De Flores R, de la Sayette V, Vivien D et al (2022) White matter hyperintensity topography in Alzheimer’s disease and links to cognition. Alzheimer’s Dementia 18:422–433PubMed

Tosto G, Zimmerman ME, Hamilton JL, Carmichael OT, Brickman AM (2015) The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment. Alzheimer’s Dementia 11:1510–1519PubMed

Wang YL, Chen W, Cai WJ, Hu H, Xu W, Wang ZT, Cao XP, Tan L, Yu JT (2020) Associations of white matter hyperintensities with cognitive decline: a longitudinal study. J Alzheimer’s Dis JAD 73:759–768PubMed

Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM (2016) Alzheimer’s disease: targeting the cholinergic system. Curr Neuropharmacol 14:101–115PubMedPubMedCentral

Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, Khachaturian AS, Vergallo A, Cavedo E, Snyder PJ et al (2018) The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain J Neurol 141:1917–1933

Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 10:122–126PubMed

10.

Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR (1982) Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science (New York, NY) 215:1237–1239

11.

Grothe M, Heinsen H, Teipel SJ (2012) Atrophy of the cholinergic Basal forebrain over the adult age range and in early stages of Alzheimer’s disease. Biol Psychiat 71:805–813PubMed

12.

Cantero JL, Zaborszky L, Atienza M (2017) Volume loss of the nucleus basalis of Meynert is associated with atrophy of innervated regions in mild cognitive impairment. Cerebral Cortex (New York, NY: 1991) 27:3881–3889

13.

Herdick M, Dyrba M, Fritz HJ, Altenstein S, Ballarini T, Brosseron F, Buerger K, Can Cetindag A, Dechent P, Dobisch L et al (2020) Multimodal MRI analysis of basal forebrain structure and function across the Alzheimer’s disease spectrum. NeuroImage Clin 28:102495PubMedPubMedCentral

14.

Selden NR, Gitelman DR, Salamon-Murayama N, Parrish TB, Mesulam MM (1998) Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain J Neurol 121(Pt 12):2249–2257

15.

Nemy M, Cedres N, Grothe MJ, Muehlboeck JS, Lindberg O, Nedelska Z, Stepankova O, Vyslouzilova L, Eriksdotter M, Barroso J et al (2020) Cholinergic white matter pathways make a stronger contribution to attention and memory in normal aging than cerebrovascular health and nucleus basalis of Meynert. Neuroimage 211:116607PubMed

16.

Schumacher J, Ray NJ, Hamilton CA, Donaghy PC, Firbank M, Roberts G, Allan L, Durcan R, Barnett N, O’Brien JT et al (2022) Cholinergic white matter pathways in dementia with Lewy bodies and Alzheimer’s disease. Brain J Neurol 145:1773–1784

17.

Nemy M, Dyrba M, Brosseron F, Buerger K, Dechent P, Dobisch L, Ewers M, Fliessbach K, Glanz W, Goerss D et al (2023) Cholinergic white matter pathways along the Alzheimer’s disease continuum. Brain J Neurol 146:2075–2088

18.

Schumacher J, Ray NJ, Hamilton CA, Bergamino M, Donaghy PC, Firbank M, Watson R, Roberts G, Allan L, Barnett N et al (2023) Free water imaging of the cholinergic system in dementia with Lewy bodies and Alzheimer’s disease. Alzheimer’s Dementia 19:4549–4563PubMed

19.

Bohnen NI, Müller ML, Kuwabara H, Constantine GM, Studenski SA (2009) Age-associated leukoaraiosis and cortical cholinergic deafferentation. Neurology 72:1411–1416PubMedPubMedCentral

20.

Jia JP, Jia JM, Zhou WD, Xu M, Chu CB, Yan X, Sun YX (2004) Differential acetylcholine and choline concentrations in the cerebrospinal fluid of patients with Alzheimer’s disease and vascular dementia. Chin Med J 117:1161–1164PubMed

21.

Wallin A, Sjögren M, Blennow K, Davidsson P (2003) Decreased cerebrospinal fluid acetylcholinesterase in patients with subcortical ischemic vascular dementia. Dement Geriatr Cogn Disord 16:200–207PubMed

22.

Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV (2002) Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet (Lond, Engl) 359:1283–1290

23.

Kim HJ, Moon WJ, Han SH (2013) Differential cholinergic pathway involvement in Alzheimer’s disease and subcortical ischemic vascular dementia. J Alzheimer’s Dis JAD 35:129–136PubMed

24.

Park HE, Park IS, Oh YS, Yang DW, Lee KS, Choi HS, Ahn KJ, Kim JS (2015) Subcortical whiter matter hyperintensities within the cholinergic pathways of patients with dementia and parkinsonism. J Neurol Sci 353:44–48PubMed

25.

Richter N, Michel A, Onur OA, Kracht L, Dietlein M, Tittgemeyer M, Neumaier B, Fink GR, Kukolja J (2017) White matter lesions and the cholinergic deficit in aging and mild cognitive impairment. Neurobiol Aging 53:27–35PubMed

26.

Jaswal G, Swardfager W, Gao F-q, Nestor SM, Ganda A, Cogo-Moreira H, Sahlas DJ, Stuss DT, Moody A, Black SE (2018) Reduced substantia innominata volume mediates contributions of microvascular and macrovascular disease to cognitive deficits in Alzheimer’s disease. Neurobiol Aging 66:23–31PubMed

27.

Kindler C, Upadhyay N, Bendella Z, Dorn F, Keil VC, Petzold GC (2023) Independent and additive contribution of white matter hyperintensities and Alzheimer’s disease pathology to basal forebrain cholinergic system degeneration. NeuroImage Clin 39:103477PubMedPubMedCentral

28.

Landau SM, Mintun MA, Joshi AD, Koeppe RA, Petersen RC, Aisen PS, Weiner MW, Jagust WJ (2012) Amyloid deposition, hypometabolism, and longitudinal cognitive decline. Ann Neurol 72:578–586PubMedPubMedCentral

29.

Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J et al (2018) NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s Dementia 14:535–562PubMed

30.

Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA (1987) MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol 149:351–356PubMed

31.

Qiu T, Hong H, Zeng Q, Luo X, Wang X, Xu X, Xie F, Li X, Li K, Huang P et al (2023) Degeneration of cholinergic white matter pathways and nucleus basalis of Meynert in individuals with objective subtle cognitive impairment. Neurobiol Aging 132:198–208PubMed

32.

Dhollander T, Connelly A (2016) A novel iterative approach to reap the benefits of multi-tissue CSD from just single-shell (+b=0) diffusion MRI data. In: Singapore: 24th international society of magnetic resonance in medicine, p 3010.

33.

Dhollander T, Raffelt D, Connelly A (2016) Unsupervised 3-tissue response function estimation from single-shell or multi-shell diffusion MR data without a co-registered T1 image. In: Proceedings of ISMRM workshop on breaking the barriers of diffusion MRI, Lisbon, Portugal, p 5

34.

Kilimann I, Grothe M, Heinsen H, Alho EJ, Grinberg L, Amaro E Jr, Dos Santos GA, da Silva RE, Mitchell AJ, Frisoni GB et al (2014) Subregional basal forebrain atrophy in Alzheimer’s disease: a multicenter study. J Alzheimer’s Dis JAD 40:687–700PubMed

35.

Avants BB, Epstein CL, Grossman M, Gee JC (2008) Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal 12:26–41PubMed

36.

Ashburner J, Friston K (2007) Non-linear registration: statistical parametric mapping. Academic Press, New York, NY

37.

Bates D, Mächler M, Bolker B, Walker S (2015) Fitting linear mixed-effects models using lme4. J Stat Softw 67:1–48

38.

Team RC, Team R (2005) A language and environment for statistical computing. R Foundation for Statistical Computing, Austria

39.

Liu Q, Zhu Z, Teipel SJ, Yang J, Xing Y, Tang Y, Jia J (2017) White matter damage in the cholinergic system contributes to cognitive impairment in subcortical vascular cognitive impairment, no dementia. Front Aging Neurosci 9:47PubMedPubMedCentral

40.

McNeely AA, Ramirez J, Nestor SM, Zhao J, Gao F, Kiss A, Stuss DT, Black SE (2015) Cholinergic subcortical hyperintensities in Alzheimer’s disease patients from the Sunnybrook Dementia Study: relationships with cognitive dysfunction and hippocampal atrophy. J Alzheimer’s Dis JAD 43:785–796PubMed

41.

Cedres N, Ferreira D, Nemy M, Machado A, Pereira JB, Shams S, Wahlund LO, Zettergren A, Stepankova O, Vyslouzilova L et al (2022) Association of cerebrovascular and Alzheimer disease biomarkers with cholinergic white matter degeneration in cognitively unimpaired individuals. Neurology 99:e1619–e1629PubMedPubMedCentral

42.

Grothe MJ, Schuster C, Bauer F, Heinsen H, Prudlo J, Teipel SJ (2014) Atrophy of the cholinergic basal forebrain in dementia with Lewy bodies and Alzheimer’s disease dementia. J Neurol 261:1939–1948PubMed

43.

Jung S, Zarow C, Mack WJ, Zheng L, Vinters HV, Ellis WG, Lyness SA, Chui HC (2012) Preservation of neurons of the nucleus basalis in subcortical ischemic vascular disease. Arch Neurol 69:879–886PubMedPubMedCentral

44.

Román GC, Kalaria RN (2006) Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia. Neurobiol Aging 27:1769–1785PubMed

45.

Kloppenborg RP, Nederkoorn PJ, Geerlings MI, van den Berg E (2014) Presence and progression of white matter hyperintensities and cognition: a meta-analysis. Neurology 82:2127–2138PubMed

46.

Hamilton OKL, Backhouse EV, Janssen E, Jochems ACC, Maher C, Ritakari TE, Stevenson AJ, Xia L, Deary IJ, Wardlaw JM (2021) Cognitive impairment in sporadic cerebral small vessel disease: A systematic review and meta-analysis. Alzheimer’s Dementia 17:665–685PubMed

47.

Pinter D, Enzinger C, Fazekas F (2015) Cerebral small vessel disease, cognitive reserve and cognitive dysfunction. J Neurol 262:2411–2419PubMed

48.

Kim MJ, Lee KM, Son YD, Jeon HA, Kim YB, Cho ZH (2012) Increased basal forebrain metabolism in mild cognitive impairment: an evidence for brain reserve in incipient dementia. J Alzheimer’s Dis JAD 32:927–938PubMed

49.

Nicolas B, Alessandra D, Daniela P, Osman R, Sara T, Giovanni BF, Valentina G (2020) Basal forebrain metabolism in Alzheimer’s disease continuum: relationship with education. Neurobiol Aging 87:70–77PubMed

Title: Effect of cerebral small vessel disease on the integrity of cholinergic system in mild cognitive impairment patients: a longitudinal study
Authors: Tiantian Qiu
Hui Hong
Qingze Zeng
Xiaopei Xu
Yanyan Wang
Lixin Zhu
Lige Zhang
Kaicheng Li
Shouping Dai
Xiaodong Li
Fei Xie
Yusong Zhang
Xiao Luo
for the Alzheimer’s Disease Neuroimaging Initiative
Publication date: 21-02-2024
Publisher: Springer Berlin Heidelberg
Keywords: Mild Neurocognitive Disorder
Alzheimer's Disease
Alzheimer's Disease
Cerebral Small Vessel Disease
Magnetic Resonance Imaging
Magnetic Resonance Imaging
Published in: Journal of Neurology / Issue 5/2024
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-024-12218-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Effect of cerebral small vessel disease on the integrity of cholinergic system in mild cognitive impairment patients: a longitudinal study

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2024

Reduced eye gaze fixation during emotion recognition among patients with temporal lobe epilepsy

Correction to: Ultra-late response (> 24 weeks) to anti-CGRP monoclonal antibodies in migraine: a multicenter, prospective, observational study

Ravulizumab treats myasthenic crisis

Artificial intelligence in neurology: opportunities, challenges, and policy implications

Identifying and understanding cognitive profiles in multiple sclerosis: a role for visuospatial memory functioning

The role of ethnicity and native-country income in multiple sclerosis: the Italian multicentre study (MS-MigIT)