Abstract
Visuospatial impairment in Parkinson’s disease (PD) heralds the onset of a progressive dementia syndrome and might be associated with cholinergic dysfunction. It remains unclear however, whether degeneration of the cholinergic basal forebrain is directly related to cognitive decline, or whether relationships between this region and cognitive function are mediated by closely related brain structures such as those in the medial temporal lobe. To evaluate relationships between structure of the cholinergic basal forebrain, medial temporal lobe and cognition, 27 PD patients without dementia and 20 controls underwent neuropsychological assessment and MRI. Volumes of the cholinergic basal forebrain nuclei, the entorhinal cortex, the hippocampus and its subfields were measured. Regression models utilised basal forebrain and hippocampal volumetric measures to predict cognitive performance. In PD, visuospatial memory (but not verbal memory or executive function) was correlated with hippocampal volume, particularly CA2-3, and basal forebrain subregion Ch1-2, but not Ch4. In addition, hippocampal volume was correlated with Ch1-2 in PD. The relationship between Ch1-2 and visuospatial memory was mediated by CA2-3 integrity. There were no correlations between cognitive and volumetric measures in controls. Our data imply that the integrity of the cholinergic basal forebrain is associated with subregional hippocampal volume. Additionally, a relationship between visuospatial function and cholinergic nuclei does exist, but is fully mediated by variations in hippocampal structure. These findings are consistent with the recent hypothesis that forebrain cholinergic system degeneration results in cognitive deficits via cholinergic denervation, and subsequent structural degeneration, of its target regions.
Similar content being viewed by others
References
Aggleton, J. P., & Brown, M. W. (2006). Interleaving brain systems for episodic and recognition memory. Trends in Cognitive Sciences, 10(10), 455–463. https://doi.org/10.1016/j.tics.2006.08.003
Agosta, F., Canu, E., Stefanova, E., Sarro, L., Tomić, A., Špica, V., et al. (2014). Mild cognitive impairment in Parkinson’s disease is associated with a distributed pattern of brain white matter damage. Human Brain Mapping, 35(5), 1921–1929. https://doi.org/10.1002/hbm.22302
Albert, M. S., DeKosky, S. T., Dickson, D., Dubois, B., Feldman, H. H., Fox, N. C., et al. (2011). 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. Alzheimer’s & Dementia, 7(3), 270–279. https://doi.org/10.1016/j.jalz.2011.03.008
Ashburner, J. (2007). A fast diffeomorphic image registration algorithm. NeuroImage, 38(1), 95–113. https://doi.org/10.1016/j.neuroimage.2007.07.007
Ashburner, J. (2009). Computational anatomy with the SPM software. Magnetic Resonance Imaging, 27(8), 1163–1174. https://doi.org/10.1016/j.mri.2009.01.006
Berlot, R., Metzler-Baddeley, C., Ikram, M. A., Jones, D. K., & O’Sullivan, M. J. (2016). Global efficiency of structural networks mediates cognitive control in mild cognitive impairment. Frontiers in Aging Neuroscience, 8(DEC). https://doi.org/10.3389/fnagi.2016.00292
Bohnen, N. I., & Albin, R. L. (2011). The cholinergic system and Parkinson disease. Behavioural Brain Research, 221(2), 564–573. https://doi.org/10.1016/j.bbr.2009.12.048
Braak, H., Del Tredici, K., Rüb, U., de Vos, R. A. I., Jansen Steur, E. N. H., & Braak, E. (2003). Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging, 24(2), 197–211.
Candy, J. M., Perry, R. H., Perry, E. K., Irving, D., Blessed, G., Fairbairn, A. F., & Tomlinson, B. E. (1983). Pathological changes in the nucleus of Meynert in Alzheimer’s and Parkinson’s diseases. Journal of the Neurological Sciences, 59(2), 277–289.
Carlesimo, G. A., Piras, F., Assogna, F., Pontieri, F. E., Caltagirone, C., & Spalletta, G. (2012). Hippocampal abnormalities and memory deficits in Parkinson disease: A multimodal imaging study. Neurology, 78(24), 1939–1945. https://doi.org/10.1212/WNL.0b013e318259e1c5
Cedres, N., Ferreira, D., Machado, A., Shams, S., Sacuiu, S., Waern, M., et al. (2020). Predicting Fazekas scores from automatic segmentations of white matter signal abnormalities. Aging, 12(1), 894–901. https://doi.org/10.18632/aging.102662
Chen, B., Fan, G. G., Liu, H., & Wang, S. (2015). Changes in anatomical and functional connectivity of Parkinson’s disease patients according to cognitive status. European Journal of Radiology, 84(7), 1318–1324. https://doi.org/10.1016/j.ejrad.2015.04.014
Churchyard, A., & Lees, A. J. (1997). The relationship between dementia and direct involvement of the hippocampus and amygdala in Parkinson’s disease. Neurology, 49(6), 1570–1576.
Dale, A. M., Fischl, B., & Sereno, M. I. (1999). Cortical surface-based analysis. I. Segmentation and Surface Reconstruction. Neuroimage, 9(2), 179–194. https://doi.org/10.1006/nimg.1998.0395
De Lacalle, S., Lim, C., Sobreviela, T., Mufson, E. J., Hersh, L. B., & Saper, C. B. (1994). Cholinergic innervation in the human hippocampal formation including the entorhinal cortex. The Journal of Comparative Neurology, 345(3), 321–344. https://doi.org/10.1002/cne.903450302
Dickson, D. W., Schmidt, M. L., Lee, V. M., Zhao, M. L., Yen, S. H., & Trojanowski, J. Q. (1994). Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease. Acta Neuropathologica, 87(3), 269–276.
Fischl, B., Sereno, M. I., & Dale, A. M. (1999). Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. NeuroImage, 9(2), 195–207. https://doi.org/10.1006/nimg.1998.0396
Foo, H., Mak, E., Chander, R. J., Ng, A., Au, W. L., Sitoh, Y. Y., et al. (2017). Associations of hippocampal subfields in the progression of cognitive decline related to Parkinson’s disease. NeuroImage. Clinical, 14, 37–42. https://doi.org/10.1016/j.nicl.2016.12.008
Forsaa, E. B., Larsen, J. P., Wentzel-Larsen, T., & Alves, G. (2010). What predicts mortality in Parkinson disease?: A prospective population-based long-term study. Neurology, 75(14), 1270–1276. https://doi.org/10.1212/WNL.0b013e3181f61311
Freund, H.-J., Kuhn, J., Lenartz, D., Mai, J. K., Schnell, T., Klosterkoetter, J., & Sturm, V. (2009). Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Archives of Neurology, 66(6), 781–785. https://doi.org/10.1001/archneurol.2009.102
Gargouri, F., Gallea, C., Mongin, M., Pyatigorskaya, N., Valabregue, R., Ewenczyk, C., et al. (2019). Multimodal magnetic resonance imaging investigation of basal forebrain damage and cognitive deficits in Parkinson’s disease. Movement Disorders, 34(4), 516–525. https://doi.org/10.1002/mds.27561
Geula, C., & Mesulam, M. (1989). Cortical cholinergic fibers in aging and Alzheimer’s disease: A morphometric study. Neuroscience, 33(3), 469–481.
Gratwicke, J., Zrinzo, L., Kahan, J., Peters, A., Beigi, M., Akram, H., et al. (2018). Bilateral Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson Disease Dementia. JAMA Neurology, 75(2), 169–178. https://doi.org/10.1001/jamaneurol.2017.3762
Grothe, M. J., Heinsen, H., Amaro, E., Grinberg, L. T., & Teipel, S. J. (2016). Cognitive correlates of basal forebrain atrophy and associated cortical hypometabolism in mild cognitive impairment. Cerebral Cortex, 26(6), 2411–2426. https://doi.org/10.1093/cercor/bhv062
Higginson, C. I., King, D. S., Levine, D., Wheelock, V. L., Khamphay, N. O., & Sigvardt, K. A. (2003). The relationship between executive function and verbal memory in Parkinson’s disease. Brain and Cognition, 52(3), 343–352.
Hughes, A. J., Daniel, S. E., Kilford, L., & Lees, A. J. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: A clinico-pathological study of 100 cases. Journal of Neurology, Neurosurgery, and Psychiatry, 55(3), 181–184.
Husain, M., & Nachev, P. (2007). Space and the parietal cortex. Trends in Cognitive Sciences, 11(1), 30–36. https://doi.org/10.1016/j.tics.2006.10.011
Iglesias, J. E., Augustinack, J. C., Nguyen, K., Player, C. M., Player, A., Wright, M., et al. (2015). A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: Application to adaptive segmentation of in vivo MRI. NeuroImage, 115, 117–137. https://doi.org/10.1016/j.neuroimage.2015.04.042
Iglesias, J. E. (2019 December 5). Segmentation of hippocampal subfields and nuclei of the amygdala (cross-sectional and longitudinal). FreeSurferWiki. FreeSurfer. https://surfer.nmr.mgh.harvard.edu/fswiki/HippocampalSubfieldsAndNucleiOfAmygdala. Accessed 10 April 2020
Imai, K., Keele, L., & Tingley, D. (2010). A general approach to causal mediation analysis. Psychological Methods, 15(4), 309–334. https://doi.org/10.1037/a0020761
Kehagia, A. A., Barker, R. A., & Robbins, T. W. (2013). Cognitive impairment in Parkinson’s disease: The dual syndrome hypothesis. Neuro-Degenerative Diseases, 11(2), 79–92. https://doi.org/10.1159/000341998
Kesner, R. P. (2013). A process analysis of the CA3 subregion of the hippocampus. Frontiers in Cellular Neuroscience, 7, 78. https://doi.org/10.3389/fncel.2013.00078
Kondo, H., & Zaborszky, L. (2016). Topographic organization of the basal forebrain projections to the perirhinal, postrhinal, and entorhinal cortex in rats. The Journal of Comparative Neurology, 524(12), 2503–2515. https://doi.org/10.1002/cne.23967
Lawrence, A. J., Chung, A. W., Morris, R. G., Markus, H. S., & Barrick, T. R. (2014). Structural network efficiency is associated with cognitive impairment in small-vessel disease. Neurology, 83(4), 304–311. https://doi.org/10.1212/WNL.0000000000000612
Lawson, R. A., Yarnall, A. J., Duncan, G. W., Breen, D. P., Khoo, T. K., Williams-Gray, C. H., et al. (2016). Cognitive decline and quality of life in incident Parkinson’s disease: The role of attention. Parkinsonism & Related Disorders, 27, 47–53. https://doi.org/10.1016/j.parkreldis.2016.04.009
Litvan, I., Goldman, J. G., Tröster, A. I., Schmand, B. A., Weintraub, D., Petersen, R. C., et al. (2012). Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: Movement Disorder Society Task Force guidelines. Movement Disorders, 27(3), 349–356. https://doi.org/10.1002/mds.24893
Mattila, P. M., Rinne, J. O., Helenius, H., & Röyttä, M. (1999). Neuritic degeneration in the hippocampus and amygdala in Parkinson’s disease in relation to Alzheimer pathology. Acta Neuropathologica, 98(2), 157–164.
McGaughy, J., Koene, R. A., Eichenbaum, H., & Hasselmo, M. E. (2005). Cholinergic deafferentation of the entorhinal cortex in rats impairs encoding of novel but not familiar stimuli in a delayed nonmatch-to-sample task. Journal of Neuroscience, 25(44), 10273–10281. https://doi.org/10.1523/JNEUROSCI.2386-05.2005
Mesulam, M. (2004). The cholinergic lesion of Alzheimer’s disease: Pivotal factor or side show? Learning & Memory, 11(1), 43–49. https://doi.org/10.1101/lm.69204
Mesulam, M.-M. (2013). Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer’s disease. The Journal of Comparative Neurology, 521(18), 4124–4144. https://doi.org/10.1002/cne.23415
Mesulam, M.-M., Mufson, E. J., Levey, A. I., & Wainer, B. H. (1983a). Cholinergic innervation of cortex by the basal forebrain: Cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. The Journal of Comparative Neurology, 214(2), 170–197. https://doi.org/10.1002/cne.902140206
Mesulam, M. M., Mufson, E. J., Wainer, B. H., & Levey, A. I. (1983b). Central cholinergic pathways in the rat: An overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience, 10(4), 1185–1201.
Molinuevo, J. L., Rabin, L. A., Amariglio, R., Buckley, R., Dubois, B., Ellis, K. A., et al. (2017). Implementation of subjective cognitive decline criteria in research studies. Alzheimer’s and Dementia, 13(3), 296–311. https://doi.org/10.1016/j.jalz.2016.09.012
Muir, J. L. (1997). Acetylcholine, aging, and Alzheimer’s disease. Pharmacology Biochemistry, and Behavior, 56(4), 687–696.
Nakashiba, T., Young, J. Z., McHugh, T. J., Buhl, D. L., & Tonegawa, S. (2008). Transgenic inhibition of synaptic transmission reveals role of CA3 output in hippocampal learning. Science (New York, N.Y.), 319(5867), 1260–1264. https://doi.org/10.1126/science.1151120
Nakazawa, K., Sun, L. D., Quirk, M. C., Rondi-Reig, L., Wilson, M. A., & Tonegawa, S. (2003). Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron, 38(2), 305–315. https://doi.org/10.1016/s0896-6273(03)00165-x
Pereira, J. B., Junqué, C., Bartrés-Faz, D., Ramírez-Ruiz, B., Marti, M.-J., & Tolosa, E. (2013). Regional vulnerability of hippocampal subfields and memory deficits in Parkinson’s disease. Hippocampus, 23(8), 720–728. https://doi.org/10.1002/hipo.22131
Ray, N. J., Bradburn, S., Murgatroyd, C., Toseeb, U., Mir, P., Kountouriotis, G. K., et al. (2018). In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson’s disease. Brain, 141(1), 165–176. https://doi.org/10.1093/brain/awx310
Sassin, I., Schultz, C., Thal, D. R., Rüb, U., Arai, K., Braak, E., & Braak, H. (2000). Evolution of Alzheimer’s disease-related cytoskeletal changes in the basal nucleus of Meynert. Acta Neuropathologica, 100(3), 259–269.
Schmitz, T. W., Nathan Spreng, R., Alzheimer’s Disease Neuroimaging Initiative, M. W., Aisen, P., Petersen, R., Jack, C. R., , et al. (2016). Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology. Nature Communications, 7, 13249. https://doi.org/10.1038/ncomms13249
Schulz, J., Pagano, G., Fernández Bonfante, J. A., Wilson, H., & Politis, M. (2018). Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson’s disease. Brain, 141(5), 1501–1516. https://doi.org/10.1093/brain/awy072
Shimada, H., Hirano, S., Shinotoh, H., Aotsuka, A., Sato, K., Tanaka, N., et al. (2009). Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology, 73(4), 273–278. https://doi.org/10.1212/WNL.0b013e3181ab2b58
Teipel, S. J., Flatz, W. H., Heinsen, H., Bokde, A. L. W., Schoenberg, S. O., Stöckel, S., et al. (2005). Measurement of basal forebrain atrophy in Alzheimer’s disease using MRI. Brain : A Journal of Neurology, 128(Pt 11), 2626–2644. https://doi.org/10.1093/brain/awh589
Trenerry, M., Crosson, B., DeBoe, J., & Leber, W. (1989). Stroop Neuropsychological Screening Test Manual. Psychological Assessment Resources (PAR).
Wardlaw, J. M., Smith, E. E., Biessels, G. J., Cordonnier, C., Fazekas, F., Frayne, R., et al. (2013, August). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. The Lancet Neurology, 12(8), 822–838. https://doi.org/10.1016/S1474-4422(13)70124-8
Weintraub, D., Doshi, J., Koka, D., Davatzikos, C., Siderowf, A. D., Duda, J. E., et al. (2011). Neurodegeneration across stages of cognitive decline in Parkinson disease. Archives of Neurology, 68(12), 1562–1568. https://doi.org/10.1001/archneurol.2011.725
Yao, N., Cheung, C., Pang, S., Shek-kwan Chang, R., Lau, K. K., Suckling, J., et al. (2016). Multimodal MRI of the hippocampus in Parkinson’s disease with visual hallucinations. Brain Structure and Function, 221(1), 287–300. https://doi.org/10.1007/s00429-014-0907-5
Funding
This work was supported by the Slovenian Research Agency (principal investigator ZP, Research Grant No. L3-4255). MJG is supported by the "Miguel Servet" program [CP19/00031] of the Spanish Instituto de Salud Carlos III (ISCIIIFEDER). NJR received funding from the Wellcome Trust and the Eleanor Countess Peel Trust.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest with respect to the research, authorship and/or publication of this article.
Ethical approval
Ethical approval for the study was provided by the Republic of Slovenia National Medical Ethics Committee.
Informed consent
All participants provided informed written consent in accordance with the Declaration of Helsinki.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Berlot, R., Pirtošek, Z., Brezovar, S. et al. Cholinergic basal forebrain and hippocampal structure influence visuospatial memory in Parkinson’s disease. Brain Imaging and Behavior 16, 118–129 (2022). https://doi.org/10.1007/s11682-021-00481-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11682-021-00481-0