Cited by 112Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsMemory and Neural Mechanisms

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The fornix and mammillary bodies in older adults with Alzheimer’s disease, mild cognitive impairment, and cognitive complaints: A volumetric MRI study.

Copenhaver, Brittany R., Rabin, Laura A., Saykin, Andrew J., Roth, Robert M., Wishart, Heather A., Flashman, Laura A., Santulli, Robert B., McHugh, Tara L., Mamourian, Alexander C.·2006·Psychiatry Research Neuroimaging

DOI 10.1016/j.pscychresns.2006.01.015

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Abstract

The fornix and mammillary bodies are important limbic structures that have not been systematically investigated in the earliest stages of preclinical dementia. The present study examined volumetric changes in the fornix and mammillary bodies and improved previously established tracing guidelines to increase reliability and provide more comprehensive measurements. Volumetric measurements were made in euthymic older adults, including 16 patients with mild Alzheimer's disease (AD), 20 patients with amnestic mild cognitive impairment (MCI), 20 individuals with cognitive complaints (CC) but normal neuropsychological test performance, and 20 demographically matched healthy controls (HC). Structural magnetic resonance imaging included a T1-weighted 1.5-mm coronal volume, acquired on a GE 1.5T LX scanner. After adjustment for total intracranial volume (ICV), significant volume reductions were observed in the fornix and mammillary bodies in patients with AD as compared with HC, CC, and MCI participants. No volume differences were seen between the HC, CC, and MCI groups. Study findings are consistent with previous research showing volume decreases of the fornix and mammillary bodies in AD, and provide new data on the relative preservation of these structures in preclinical disease stages. Results suggest that atrophy of the fornix and mammillary bodies becomes apparent at the point of conversion from MCI to AD. Longitudinal assessments are needed to delineate the time course and extent of the observed volumetric changes.

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Prevalence of Asymmetry of Mamillary Body and Fornix Size on MR Imaging
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“Abnormalities and Diseases of the Mamillary Bodies and Fornix Although acquired diseases of the mamillary bodies have been well studied (eg, MTS, Wernicke encephalopathy), there are a few reported cases of congenital malformation of these structures.(18-20) Congenital morphologic abnormalities of the mamillary body th…”
Background
Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer’s disease
Huang, W., Peng, Z., Murdock, M. H., Liu, L., Mathys, H., Dávila-Velderrain, J., Jiang, X., Chen, M., Ng, A. P., Kim, T., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.abq1019 · Cited by 26
Brain network remodelling reflects tau-related pathology prior to memory deficits in Thy-Tau22 mice
Degiorgis, L., Karatas, M., Sourty, M., Faivre, É., Lamy, J., Noblet, V., Bienert, T., Reisert, M., von Elverfeldt, D., Buée, L., et al. (2020) · Brain · doi:10.1093/brain/awaa312 · Cited by 27
The volumes of the fornix in schizophrenia and affective disorders: A post-mortem study
Brisch, R., Bernstein, H., Stauch, R., Dobrowolny, H., Krell, D., Truebner, K., Meyer-Lotz, G., Bielau, H., Steiner, J. H., Kropf, S., et al. (2008) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2007.12.007 · Cited by 25
Human subiculo-fornico-mamillary system in Alzheimer’s disease: Tau seeding by the pillar of the fornix
Brainbank Neuro-CEB Neuropathology Network, Thierry, M., Boluda, S., Delatour, B., Marty, S., Seilhean, D., Potier, M., & Duyckaerts, C. J. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02108-7 · Cited by 26
Determination of Imaging Biomarkers to Decipher Disease Trajectories and Differential Diagnosis of Neurodegenerative Diseases (DIsease TreND)
Singh, G., Lakshminarayanan, S., & Lim, E. C. (2018) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2018.05.009 · Cited by 22
Thiamine deficiency related microstructural brain changes in acute and acute-on-chronic liver failure of non-alcoholic etiology
Gupta, R. K., Yadav, S. K., Saraswat, V. A., Rangan, M., Srivastava, A., Yadav, A., Trivedi, R., Yachha, S. K., & Rathore, R. K. S. (2011) · Clinical Nutrition · doi:10.1016/j.clnu.2011.11.018 · Cited by 22
Connectome-derived diffusion characteristics of the fornix in Alzheimer's disease
Perea, R. D., Rabin, J. S., Fujiyoshi, M. G., Neal, T. E., Smith, E. E., Dijk, K. R. A. V., & Hedden, T. (2018) · NeuroImage Clinical · doi:10.1016/j.nicl.2018.04.029 · Cited by 20
“We note that this is inconsistent with previous fornix volume findings using manual tracing or semi-automatic atlas methods (Copenhaver et al., 2006; Amaral et al., 2016).”
MethodInfluential
Abnormal white matter integrity in Papez circuit in first-episode medication-naive adults with anxious depression: A combined voxel-based analysis and region of interest study
Li, M., Wu, F., Cao, Y., Jiang, X., Kong, L., & Tang, Y. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.12.149 · Cited by 21
Mammillary body regulates state-dependent fear by alternating cortical oscillations
Jiang, J., Wang, G., Luo, W., Xie, H. B., & Guan, J. (2018) · Scientific Reports · doi:10.1038/s41598-018-31622-z · Cited by 20
Brain tissue modifications induced by cholinergic therapy in Alzheimer's disease
Bozzali, M., Parker, G. J. M., Spanò, B., Serra, L., Giulietti, G., Perri, R., Magnani, G., Marra, C., Vita, M. G., Caltagirone, C., et al. (2012) · Human Brain Mapping · doi:10.1002/hbm.22130 · Cited by 19
“On the other hand, the fornix was previously reported to be critical for the conversion from MCI to AD [Copenhaver et al., 2006].”
Background
Memory Complaints with and without Memory Impairment: The Impact of Leukoaraiosis on Cognition
Lamar, M., Dannhauser, T. M., Walker, Z., Rodda, J. E., Cutinha, D. J., & Shergill, S. S. (2011) · Journal of the International Neuropsychological Society · doi:10.1017/s1355617711001123 · Cited by 17
“, 2008), and functional (Rodda, Dannhauser, Cutinha, Shergill, & Walker, 2009) MRI-based assessments of brain integrity; but not in all (Archer et al., 2006; Copenhaver et al., 2006) studies.”
Background
Hypothalamic atrophy and structural covariance in amnestic mild cognitive impairment and Alzheimer’s dementia
Pecher, H., Storch, M., Beyer, F., Witte, A. V., Baasner, C.-F., Schönknecht, P. O. D., & Weise, C. M. (2024) · NeuroImage Clinical · doi:10.1016/j.nicl.2024.103687 · Cited by 18
“…biomarker in AD (Scheltens et al. 2016; Jack et al. 2013; Colliot et al. 2008; Whitwell et al. 2011), however, volumetric studies also suggest that AD might be associated with hypothalamic atrophy even early in the disease course (Baron et al. 2001; Copenhaver et al. 2006; Hall et al. 2008).”
FDG-PET assessment of the locus coeruleus in Alzheimer’s disease
Liu, K. Y., Acosta‐Cabronero, J., Hong, Y. T., Yi, Y., Hämmerer, D., & Howard, R. J. (2021) · Neuroimage Reports · doi:10.1016/j.ynirp.2020.100002 · Cited by 17
“To also account for the possibility that the LC is smaller in AD compared to HCs, resulting in a higher proportion of lower intensity voxels due to atrophy alone, we extracted the maximum (98th percentile) SUVR values from the LC and mammillary bodies ROIs, as both are relatively small ROIs and known to undergo signif…”
Cognitive behavioral therapy (CBT) for preventing Alzheimer’s disease
Reid, L. D., Avens, F. E., & Walf, A. A. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.07.024 · Cited by 16
“Disease of the mammillary bodies and fornix (a major link to the hippocampus) have been linked to AD [82,83].”
Increased Neuronal Nuclear and Perikaryal Size in the Medial Mamillary Nucleus of Vascular Dementia and Alzheimer’s Disease Patients: Relation to Nuclear Estrogen Receptor α
Ishunina, T. A., Николаевна, Б. И., & Swaab, D. F. (2019) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000500244 · Cited by 14
Full diffusion characterization implicates regionally disparate neuropathology in Mild Cognitive Impairment
Boespflug, E. L., Storrs, J. M., Sadat-Hossieny, S., Eliassen, J. C., Shidler, M. D., Norris, M. M., & Krikorian, R. (2013) · Brain Structure and Function · doi:10.1007/s00429-013-0506-x · Cited by 14
“…with those of other studies which also found similar diffusivity profiles to reflect ongoing structural degradation with progressing disease status (Acosta-Cabronero et al. 2010; Copenhaver et al. 2006; Huang et al. 2012; Mielke et al. 2009; Oishi et al. 2012; Wang et al. 2012; Sexton et al. 2010).”
BackgroundMethodResultInfluential
Longitudinal hippocampal and extra-hippocampal microstructural and macrostructural changes following temporal lobe epilepsy surgery
Elliott, C., Gross, D. W., Wheatley, B. M., Beaulieu, C., & Sankar, T. (2018) · Epilepsy Research · doi:10.1016/j.eplepsyres.2018.01.008 · Cited by 13
Diffusion characteristics of the fornix in patients with Alzheimer’s disease
Tang, S. X., Feng, Q., Wang, G. H., Duan, S., Shan, B., & Dai, J. (2016) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2016.09.012 · Cited by 12
Age-dependent microstructure alterations in 5xFAD mice by high-resolution diffusion tensor imaging
Maharjan, S., Tsai, A. P., Lin, P. B., Ingraham, C., Jewett, M. R., Landreth, G. E., Oblak, A. L., & Wang, N. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.964654 · Cited by 15
Symmetry of the fornix using diffusion tensor imaging
Sboto‐Frankenstein, U., Lazar, T., Bolster, R. B., Thind, S., de Gervai, P. D., Gruwel, M. L. H., Smith, S. D., & Tomanek, B. (2013) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.24424 · Cited by 10
MRI anatomical variants of mammillary bodies
Tagliamonte, M., Sestieri, C., Romani, G. L., Gallucci, M., & Caulo, M. (2013) · Brain Structure and Function · doi:10.1007/s00429-013-0639-y · Cited by 10
Two distinct cell types of the medial mammillary body forming segregated subcircuits
Liu, H., Shi, Y., Zhang, Q., Yue, M.-H., Qi, Y., Xu, B., Jing, J., Zhang, L., Yang, K., Zheng, M., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03079-w · Cited by 8
The historical evolution of the fornix and its terminology: a review
Doğan, E., Güngör, A., Doğulu, F. H., & Türe, U. (2021) · Neurosurgical Review · doi:10.1007/s10143-021-01635-w · Cited by 7
Mammillary body and hypothalamic volumes in mood disorders
Nowak, M., Schindler, S., Storch, M., Geyer, S., & Schönknecht, P. (2022) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2022.12.004 · Cited by 6
Susceptibility and Volume Measures of the Mammillary Bodies Between Mild Cognitively Impaired Patients and Healthy Controls
Jin, Z., Sethi, S. K., Li, B., Tang, R., Li, Y., Hsu, C. C.-T., He, N., Haacke, E. M., & Yan, F. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.572595 · Cited by 5
“The latter finding is consistent with previous research (Copenhaver et al., 2006) showing no significant volume differences between HC and MCI groups.”
Result
The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset
Forno, G., Contador, J., Pérez‐Millan, A., Guillén, N., Falgàs, N., Sarto, J., Tort‐Merino, A., Castellví, M., Bosch, B., Fernández‐Villullas, G., et al. (2022) · European Journal of Neurology · doi:10.1111/ene.15657 · Cited by 7
“Whilst some of the previous studies have shown MB shrinkage in AD compared to healthy controls [27, 28], others have been unable to replicate those findings [21].”
Result
Could the Fornix Be Used To Predict Cognitive Impairment In the Elderly?
Fletcher, E. M. (2013) · Future Neurology · doi:10.2217/fnl.13.63 · Cited by 6
Brain Diffusion Changes in Patients Diagnosed with Alzheimers Disease
Ito, S. (2008) · Current Medical Imaging Formerly Current Medical Imaging Reviews · doi:10.2174/157340508786404116 · Cited by 6
Impact of Mesial Temporal Lobe Resection on Brain Structure in Medically Refractory Epilepsy
Elias, G. J. B., Germann, J., Neudorfer, C., Namasivayam, A. A., Loh, A., Gramer, R., Ibrahim, G. M., Valiante, T. A., Tomaszczyk, J. C., McAndrews, M. P., et al. (2021) · World Neurosurgery · doi:10.1016/j.wneu.2021.06.039 · Cited by 6
Hypothalamic imaging in Alzheimer’s disease and Lewy body dementia: A systematic review and meta-analysis
Laurell, A. A. S., Shah, S., Rahmati, M., O'Brien, J. T., & Underwood, B. R. (2025) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2025.07.011 · Cited by 5
“Two studies which initially appeared to meet the inclusion criteria demonstrated that the volume and metabolism of the mamillary bodies, which are part of the posterior hypothalamus, was reduced in people with AD compared to controls (Copenhaver et al., 2006; Nestor et al., 2003).”
Korsakoff’s Syndrome and Alzheimer’s Disease—Commonalities and Specificities of Volumetric Brain Alterations within Papez Circuit
Segobin, S. H., Ambler, M., Lanièpce, A., Platel, H., Chételat, G., Groussard, M., & Pitel, A. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12093147 · Cited by 5
“Mammillary body shrinkage has also been reported in AD with up to 25% of volume loss [43], but not in patients with Mild Cognitive Impairment [44].”
Background
Age dependent path integration deficit in 5xFAD mice
Mar, K. D., So, C., Hou, Y., & Kim, J. C. (2024) · Behavioural Brain Research · doi:10.1016/j.bbr.2024.114919 · Cited by 5
“Consistently, in human patients with mild AD, morphological changes in the MB have been identified [36], and volumetric imaging studies have also demonstrated decreased volume in the fornix and MB in older adults in the earliest stages of pre-clinical dementia [37,38].”
BackgroundMethod
A systemic review on the changes in fornix in MCI and AD conditions measured using structural MR imaging
Ali, A., Ronickom, J. F. A., & Swaminathan, R. (2025) · International Journal of Advances in Engineering Sciences and Applied Mathematics · doi:10.1007/s12572-024-00385-4 · Cited by 3
“Copenhaver et al., [30] calculated the volumes of the fornix as well as the mammillary bodies and observed that the atrophy in the fornix shows the conversion from MCI to AD.”
Influential
Endoscopic Endonasal Approach to the Third Ventricle Using the Surgical Corridor of the Reverse Third Ventriculostomy: Anatomo-Surgical Nuances
Karadağ, A., Çamlar, M., Turkis, O. F., Bayramlı, N., Middlebrooks, E. H., & Tanrıöver, N. (2022) · Journal of Neurological Surgery Part B Skull Base · doi:10.1055/a-1808-1359 · Cited by 3
Structural and functional neuroimaging throughout the lifespan
McDonald, B. C., & Saykin, A. J. (2010) · Cambridge University Press eBooks · doi:10.1017/cbo9780511674815.007 · Cited by 3
Volume Loss in the Mammillary Bodies, Fornix, and Other Papez Circuit Structures in Fighters with Traumatic Encephalopathy Syndrome
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P1‐033: Hippocampal sclerosis dementia
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Zhang, X., Guan, Q., Li, Y.-J., Zhang, J.-F., Zhu, W.-L., Luo, Y.-J., & Zhang, H. (2022) · Journal of Alzheimer's Disease · doi:10.3233/jad-215649 · Cited by 3
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3D Mapping Reveals Network-specific Amyloid Progression and Subcortical SusceptibilityPreprint
Canter, R. G., Choi, H., Wang, J., Watson, L. A., Yao, C., Abdurrob, F., Bousleiman, S. M., Delalle, I., Chung, K., & Tsai, L.-H. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/116244 · Cited by 2
Alzheimer’s Disease: Neurostructures
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Hypothalamic structure and function in Alzheimer’s disease and Lewy-body dementia: a systematic review and meta-analysisPreprint
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Regional- and cell type-specific changes of the human brain during aging
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“78 The corpus callosum (CC) is the largest white matter nerve tract found in the human brain, 79 responsible for the communication and interaction be-tween the two halves of the brain.”
Background

Authors: Copenhaver, B. R., Rabin, L. A., Saykin, A. J., Roth, R. M., Wishart, H. A., Flashman, L. A., Santulli, R. B., McHugh, T. L., & Mamourian, A. C.
Affiliations: Dartmouth College (US)
Dartmouth–Hitchcock Medical Center (US)
Corresponding author: Saykin, Andrew J.
ORCID: Saykin, Andrew J.
Roth, Robert M.
Flashman, Laura A.
Santulli, Robert B.
Mamourian, Alexander C.
Venue: Psychiatry Research Neuroimaging
Publisher: Elsevier BV
Published: 2006-10
Volume: 147
Issue: 2-3
Pages: 93-103
ISSN: 0925-4927 (ISSN-L)
DOI: 10.1016/j.pscychresns.2006.01.015
OpenAlex: W1979535807
Cited by: 112
References: 54
Citations by year: 2026: 2 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 8 · 2021: 7 · 2020: 9 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 7 · 2015: 4 · 2014: 5 · 2013: 11 · 2012: 3
FWCI: 3.83
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Psychiatry Research Neuroimaging (publishedVersion)
PubMed (publishedVersion)
Funders: Dartmouth-Hitchcock Medical Center
National Institute on Aging (R01 AG19771, R01AG019771)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords: fornix, mammillary bodies, Alzheimer's disease, mild cognitive impairment, cognitive complaints, preclinical dementia, limbic system, brain atrophy, volumetric MRI
MeSH terms: Aged, Alzheimer Disease, Cognition Disorders, Demography, Female, Humans, Magnetic Resonance Imaging, Male, Mammillary Bodies, Neuropsychological Tests, Severity of Illness Index, Fornix, Brain, Plaque, Amyloid

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The fornix and mammillary bodies in older adults with Alzheimer’s disease, mild cognitive impairment, and cognitive complaints: A volumetric MRI study.

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