Background: The hippocampus, entorhinal cortex (EC), and basal forebrain (BF) are among the earliest regions affected by Alzheimer's disease (AD) pathology. They play an essential role in spatial pattern separation, a process critical for accurate discrimination between similar locations. Objective: We examined differences in spatial pattern separation performance between older adults with amnestic mild cognitive impairment (aMCI) with AD versus those with non-Alzheimer's pathologic change (non-AD) and interrelations between volumes of the hippocampal, EC subregions and BF nuclei projecting to these subregions (medial septal nuclei and vertical limb of the diagonal band of Broca - Ch1-2 nuclei) with respect to performance. Methods: Hundred and eighteen older adults were recruited from the Czech Brain Aging Study. Participants with AD aMCI (n = 37), non-AD aMCI (n = 26), mild AD dementia (n = 26), and cognitively normal older adults (CN; n = 29) underwent spatial pattern separation testing, cognitive assessment and brain magnetic resonance imaging. Results: The AD aMCI group had less accurate spatial pattern separation performance than the non-AD aMCI (p = 0.039) and CN (p < 0.001) groups. The AD aMCI and non-AD groups did not differ in other cognitive tests. Decreased BF Ch1-2 volume was indirectly associated with worse performance through reduced hippocampal tail volume and reduced posteromedial EC and hippocampal tail or body volumes operating in serial. Conclusion: The study demonstrates that spatial pattern separation testing differentiates AD biomarker positive and negative older adults with aMCI and provides evidence that BF Ch1-2 nuclei influence spatial pattern separation through the posteromedial EC and the posterior hippocampus.

International Clinical Research Center St Anne's University Hospital Brno Brno Czechia

Memory Clinic Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czechia

Zobrazit více v PubMed

Aggleton P. J., Wright N. F., Vann S. D., Saunders R. C. (2012). Medial temporal lobe projections to the retrosplenial cortex of the macaque monkey. Hippocampus 22 1883–1900. 10.1002/HIPO.22024 PubMed DOI PMC

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. Alzheimers Dement. 7 270–279. 10.1016/j.jalz.2011.03.008 PubMed DOI PMC

Ally B. A., Hussey E. P., Ko P. C., Molitor R. J. (2013). Pattern separation and pattern completion in Alzheimer’s disease: evidence of rapid forgetting in amnestic mild cognitive impairment. Hippocampus 23 1246–1258. 10.1002/HIPO.22162 PubMed DOI PMC

Ashburner J. (2007). A fast diffeomorphic image registration algorithm. Neuroimage 38 95–113. 10.1016/j.neuroimage.2007.07.007 PubMed DOI

Berron D., Cardenas-Blanco A., Bittner D., Metzger C. D., Spottke A., Heneka M. T., et al. (2019). Higher CSF tau levels are related to hippocampal hyperactivity and object mnemonic discrimination in older adults. J. Neurosci. 39 8788–8798. 10.1523/JNEUROSCI.1279-19.2019 PubMed DOI PMC

Berron D., Neumann K., Maass A., Schütze H., Fliessbach K., Kiven V., et al. (2018). Age-related functional changes in domain-specific medial temporal lobe pathways. Neurobiol. Aging 65 86–97. 10.1016/J.NEUROBIOLAGING.2017.12.030 PubMed DOI

Berron D., Vieweg P., Hochkeppler A., Pluta J. B., Ding S. L., Maass A., et al. (2017). A protocol for manual segmentation of medial temporal lobe subregions in 7 Tesla MRI. NeuroImage Clin. 15 466–482. 10.1016/J.NICL.2017.05.022 PubMed DOI PMC

Braak H., Braak E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82 239–259. PubMed

Braak H., Braak E. (1997). Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18 351–357. 10.1016/S0197-4580(97)00056-0 PubMed DOI

Burwell R. D. (2000). The parahippocampal region: corticocortical connectivity. Ann. N. Y. Acad. Sci. 911 25–42. 10.1111/J.1749-6632.2000.TB06717.X PubMed DOI

Cerman J., Laczó J., Vyhnálek M., Malinovská J., Hanzalová J., Hort J. (2020). Cerebrospinal fluid ratio of phosphorylated tau protein and beta amyloid predicts amyloid PET positivity. Cesk. Slov. Neurol. N. 83 173–179. 10.14735/amcsnn2020173 DOI

Coughlan G., Laczó J., Hort J., Minihane A. M., Hornberger M. (2018). Spatial navigation deficits — Overlooked cognitive marker for preclinical Alzheimer disease? Nat. Rev. Neurol. 14 496–506. 10.1038/s41582-018-0031-x PubMed DOI

Crary J. F., Trojanowski J. Q., Schneider J. A., Abisambra J. F., Abner E. L., Alafuzoff I., et al. (2014). Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128 755–766. 10.1007/S00401-014-1349-0 PubMed DOI PMC

Desikan S., Koser D. E., Neitz A., Monyer H. (2018). Target selectivity of septal cholinergic neurons in the medial and lateral entorhinal cortex. Proc. Natl. Acad. Sci. U.S.A. 115 E2644–E2652. 10.1073/PNAS.1716531115 PubMed DOI PMC

Doan T. P., Lagartos-Donate M. J., Nilssen E. S., Ohara S., Witter M. P. (2019). Convergent projections from perirhinal and postrhinal cortices suggest a multisensory nature of lateral, but not medial, entorhinal cortex. Cell Rep. 29 617.e7–627.e7. 10.1016/J.CELREP.2019.09.005 PubMed DOI

Fernández-Cabello S., Kronbichler M., Van Dijk K. R. A., Goodman J. A., Spreng R. N., Schmitz T. W. (2020). Basal forebrain volume reliably predicts the cortical spread of Alzheimer’s degeneration. Brain 143 993–1009. 10.1093/BRAIN/AWAA012 PubMed DOI PMC

Ferrer I., Santpere G., van Leeuwen F. W. (2008). Argyrophilic grain disease. Brain 131 1416–1432. 10.1093/BRAIN/AWM305 PubMed DOI

Flanagan E. C., Wong S., Dutt A., Tu S., Bertoux M., Irish M., et al. (2016). False recognition in behavioral variant frontotemporal dementia and Alzheimer’s disease-disinhibition or amnesia? Front. Aging Neurosci. 8:177. 10.3389/fnagi.2016.00177 PubMed DOI PMC

Fleisher A. S., Chen K., Liu X., Ayutyanont N., Roontiva A., Thiyyagura P., et al. (2013). Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol. Aging 34 1–12. 10.1016/J.NEUROBIOLAGING.2012.04.017 PubMed DOI

Geula C., Nagykery N., Nicholas A., Wu C. K. (2008). Cholinergic neuronal and axonal abnormalities are present early in aging and in Alzheimer disease. J. Neuropathol. Exp. Neurol. 67 309–318. 10.1097/NEN.0B013E31816A1DF3 PubMed DOI PMC

Gilbert P. E., Kesner R. P. (2006). The role of the dorsal CA3 hippocampal subregion in spatial working memory and pattern separation. Behav. Brain Res. 169 142–149. 10.1016/j.bbr.2006.01.002 PubMed DOI

Giocomo L. M., Hasselmo M. E. (2007). Neuromodulation by glutamate and acetylcholine can change circuit dynamics by regulating the relative influence of afferent input and excitatory feedback. Mol. Neurobiol. 36 184–200. 10.1007/s12035-007-0032-z PubMed DOI

Grothe M. J., Ewers M., Krause B., Heinsen H., Teipel S. J. (2014). Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects. Alzheimers Dement. 10 S344–S353. 10.1016/J.JALZ.2013.09.011 PubMed DOI PMC

Güsten J., Ziegler G., Düzel E., Berron D. (2021). Age impairs mnemonic discrimination of objects more than scenes: a web-based, large-scale approach across the lifespan. Cortex 137 138–148. 10.1016/J.CORTEX.2020.12.017 PubMed DOI

Hayes A. (2013). Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-Based Approach. New York, NY: The Guilford Press.

Holden H. M., Hoebel C., Loftis K., Gilbert P. E. (2012). Spatial pattern separation in cognitively normal young and older adults. Hippocampus 22 1826–1832. 10.1002/hipo.22017 PubMed DOI PMC

Howett D., Castegnaro A., Krzywicka K., Hagman J., Marchment D., Henson R., et al. (2019). Differentiation of mild cognitive impairment using an entorhinal cortex-based test of virtual reality navigation. Brain 142 1751–1766. 10.1093/brain/awz116 PubMed DOI PMC

Hunsaker M. R., Kesner R. P. (2008). Evaluating the differential roles of the dorsal dentate gyrus, dorsal CA3, and dorsal CA1 during a temporal ordering for spatial locations task. Hippocampus 18 955–964. 10.1002/hipo.20455 PubMed DOI PMC

Hunsaker M. R., Kesner R. P. (2013). The operation of pattern separation and pattern completion processes associated with different attributes or domains of memory. Neurosci. Biobehav. Rev. 37 36–58. 10.1016/j.neubiorev.2012.09.014 PubMed DOI

Hyman B. T., Phelps C., Beach T. G., Bigio E. H., Cairns N. J., Carrillo M. C., et al. (2012). National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 8 1–13. 10.1016/J.JALZ.2011.10.007 PubMed DOI PMC

Ikonen S., McMahan R., Gallagher M., Eichenbaum H., Tanila H. (2002). Cholinergic system regulation of spatial representation by the hippocampus. Hippocampus 12 386–397. 10.1002/hipo.1109 PubMed DOI

Jack C. R., Jr., Petersen R. C., O’Brien P. C., Tangalos E. G. (1992). MR-based hippocampal volumetry in the diagnosis of Alzheimer’s disease. Neurology 42 183–188. PubMed

Jack C. R., Bennett D. A., Blennow K., Carrillo M. C., Dunn B., Haeberlein S. B., et al. (2018). NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14 535–562. 10.1016/J.JALZ.2018.02.018 PubMed DOI PMC

Jacobs H. I. L., Hedden T., Schultz A. P., Sepulcre J., Perea R. D., Amariglio R. E., et al. (2018). Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat. Neurosci. 21 424–431. 10.1038/S41593-018-0070-Z PubMed DOI PMC

Josephs K. A., Murray M. E., Tosakulwong N., Whitwell J. L., Knopman D. S., Machulda M. M., et al. (2017). Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART). Acta Neuropathol. 133 705–715. 10.1007/s00401-017-1681-2 PubMed DOI PMC

Kesner R. P., Hopkins R. O. (2006). Mnemonic functions of the hippocampus: a comparison between animals and humans. Biol. Psychol. 73 3–18. 10.1016/j.biopsycho.2006.01.004 PubMed DOI

Kilimann I., Grothe M., Heinsen H., Alho E. J. L., Grinberg L., Amaro E., Jr., et al. (2014). Subregional basal forebrain atrophy in Alzheimer’s disease: a multicenter Study. J. Alzheimers. Dis. 40 687–700. 10.3233/JAD-132345 PubMed DOI PMC

Kondo H., Zaborszky L. (2016). Topographic organization of the basal forebrain projections to the perirhinal, postrhinal, and entorhinal cortex in rats. J. Comp. Neurol. 524 2503–2515. 10.1002/CNE.23967 PubMed DOI PMC

Kravitz D. J., Saleem K. S., Baker C. I., Mishkin M. (2011). A new neural framework for visuospatial processing. Nat. Rev. Neurosci. 12 217–230. 10.1038/NRN3008 PubMed DOI PMC

Larrabee G. J., Youngjohn J. R., Sudilovsky A., Crook T. H. (1993). Accelerated forgetting in Alzheimer-type dementia. J. Clin. Exp. Neuropsychol. 15 701–712. 10.1080/01688639308402590 PubMed DOI

Leal S. L., Yassa M. A. (2018). Integrating new findings and examining clinical applications of pattern separation. Nat. Neurosci. 21 163–173. 10.1038/S41593-017-0065-1 PubMed DOI PMC

Lee A. C., Scahill V. L., Graham K. S. (2008). Activating the medial temporal lobe during oddity judgment for faces and scenes. Cereb. Cortex 18 683–696. 10.1093/CERCOR/BHM104 PubMed DOI

Lee H., Stirnberg R., Wu S., Wang X., Stöcker T., Jung S., et al. (2020). Genetic Alzheimer’s disease risk affects the neural mechanisms of pattern separation in hippocampal subfields. Curr. Biol. 30 4201.e3–4212.e3. 10.1016/J.CUB.2020.08.042 PubMed DOI

Libby L. A., Ekstrom A. D., Ragland J. D., Ranganath C. (2012). Differential connectivity of perirhinal and parahippocampal cortices within human hippocampal subregions revealed by high-resolution functional imaging. J. Neurosci. 32 6550–6560. 10.1523/JNEUROSCI.3711-11.2012 PubMed DOI PMC

Lindberg O., Mårtensson G., Stomrud E., Palmqvist S., Wahlund L. O., Westman E., et al. (2017). Atrophy of the posterior subiculum is associated with memory impairment, Tau- and Aβ pathology in non-demented individuals. Front. Aging Neurosci. 9:306. 10.3389/FNAGI.2017.00306 PubMed DOI PMC

Lladó A., Tort-Merino A., Sánchez-Valle R., Falgàs N., Balasa M., Bosch B., et al. (2018). The hippocampal longitudinal axis-relevance for underlying tau and TDP-43 pathology. Neurobiol. Aging 70 1–9. 10.1016/J.NEUROBIOLAGING.2018.05.035 PubMed DOI

Maass A., Berron D., Harrison T. M., Adams J. N., La Joie R., Baker S., et al. (2019). Alzheimer’s pathology targets distinct memory networks in the ageing brain. Brain 142 2492–2509. 10.1093/BRAIN/AWZ154 PubMed DOI PMC

Maass A., Berron D., Libby L. A., Ranganath C., Düzel E. (2015). Functional subregions of the human entorhinal cortex. eLife 4:e06426. 10.7554/ELIFE.06426 PubMed DOI PMC

Mckhann G. M., Knopman D. S., Chertkow H., Hyman B. T., Jack C. R., Jr., Kawas C. H., et al. (2011). The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup. Alzheimers Dement. 7 263–269. 10.1016/j.jalz.2011.03.005 PubMed DOI PMC

McTighe S. M., Mar A. C., Romberg C., Bussey T. J., Saksida L. M. (2009). A new touchscreen test of pattern separation: effect of hippocampal lesions. Neuroreport 20 881–885. 10.1097/WNR.0B013E32832C5EB2 PubMed DOI

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 1185–1201. PubMed

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. J. Comp. Neurol. 214 170–197. 10.1002/cne.902140206 PubMed DOI

Nadel L., Hoscheidt S., Ryan L. R. (2013). Spatial cognition and the hippocampus: the anterior-posterior axis. J. Cogn. Neurosci. 25 22–28. 10.1162/JOCN_A_00313 PubMed DOI

Navarro Schröder T., Haak K. V., Zaragoza Jimenez N. I., Beckmann C. F., Doeller C. F. (2015). Functional topography of the human entorhinal cortex. eLife 4:e06738. 10.7554/ELIFE.06738 PubMed DOI PMC

Nilssen E. S., Doan T. P., Nigro M. J., Ohara S., Witter M. P. (2019). Neurons and networks in the entorhinal cortex: a reappraisal of the lateral and medial entorhinal subdivisions mediating parallel cortical pathways. Hippocampus 29 1238–1254. 10.1002/HIPO.23145 PubMed DOI

Olsen R. K., Yeung L. K., Noly-Gandon A., D’Angelo M. C., Kacollja A., Smith V. M., et al. (2017). Human anterolateral entorhinal cortex volumes are associated with cognitive decline in aging prior to clinical diagnosis. Neurobiol. Aging 57 195–205. 10.1016/J.NEUROBIOLAGING.2017.04.025 PubMed DOI

Palmqvist S., Schöll M., Strandberg O., Mattsson N., Stomrud E., Zetterberg H., et al. (2017). Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat. Commun. 8:1214. 10.1038/s41467-017-01150-x PubMed DOI PMC

Parizkova M., Lerch O., Andel R., Kalinova J., Markova H., Vyhnalek M., et al. (2020). Spatial pattern separation in early Alzheimer’s disease. J. Alzheimers. Dis. 76 121–138. 10.3233/JAD-200093 PubMed DOI

Parizkova M., Lerch O., Moffat S. D., Andel R., Mazancova A. F., Nedelska Z., et al. (2018). The effect of Alzheimer’s disease on spatial navigation strategies. Neurobiol. Aging 64 107–115. 10.1016/j.neurobiolaging.2017.12.019 PubMed DOI

Pengas G., Patterson K., Arnold R. L., Bird C. M., Burgess N., Nestor P. J. (2010). Lost and found: bespoke memory testing for Alzheimer’s disease and semantic dementia. J. Alzheimers. Dis. 21 1347–1365. 10.3233/JAD-2010-100654 PubMed DOI

Pihlajamäki M., Tanila H., Könönen M., Hänninen T., Hämäläinen A., Soininen H., et al. (2004). Visual presentation of novel objects and new spatial arrangements of objects differentially activates the medial temporal lobe subareas in humans. Eur. J. Neurosci. 19 1939–1949. 10.1111/J.1460-9568.2004.03282.X PubMed DOI

Race E., LaRocque K. F., Keane M. M., Verfaellie M. (2013). Medial temporal lobe contributions to short-term memory for faces. J. Exp. Psychol. Gen. 142 1309–1322. 10.1037/A0033612 PubMed DOI PMC

Reagh Z. M., Ho H. D., Leal S. L., Noche J. A., Chun A., Murray E. A., et al. (2016). Greater loss of object than spatial mnemonic discrimination in aged adults. Hippocampus 26 417–422. 10.1002/HIPO.22562 PubMed DOI PMC

Reagh Z. M., Noche J. A., Tustison N. J., Delisle D., Murray E. A., Yassa M. A. (2018). Functional imbalance of anterolateral entorhinal cortex and hippocampal dentate/CA3 underlies age-related object pattern separation deficits. Neuron 97 1187.e4–1198.e4. 10.1016/J.NEURON.2018.01.039 PubMed DOI PMC

Reagh Z. M., Roberts J. M., Ly M., DiProspero N., Murray E., Yassa M. A. (2014). Spatial discrimination deficits as a function of mnemonic interference in aged adults with and without memory impairment. Hippocampus 24 303–314. 10.1002/hipo.22224 PubMed DOI PMC

Reagh Z. M., Yassa M. A. (2014). Object and spatial mnemonic interference differentially engage lateral and medial entorhinal cortex in humans. Proc. Natl. Acad. Sci. U.S.A. 111 E4264–E4273. 10.1073/PNAS.1411250111 PubMed DOI PMC

Ryan L., Cardoza J. A., Barense M. D., Kawa K. H., Wallentin-Flores J., Arnold W. T., et al. (2012). Age-related impairment in a complex object discrimination task that engages perirhinal cortex. Hippocampus 22 1978–1989. 10.1002/hipo.22069 PubMed DOI PMC

Sassin I., Schultz C., Thal D. R., Rüb U., Arai K., Braak E., et al. (2000). Evolution of Alzheimer’s disease-related cytoskeletal changes in the basal nucleus of Meynert. Acta Neuropathol. 100 259–269. 10.1007/s004019900178 PubMed DOI

Saunders A. M., Hulette C., Welsh-Bohmer K. A., Schmechel D. E., Crain B., Burke J. R., et al. (1996). Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer’s disease. Lancet 348 90–93. 10.1016/S0140-6736(96)01251-2 PubMed DOI

Schmidt M. F., Storrs J. M., Freeman K. B., Jack C. R., Jr., Turner S. T. (2018). A comparison of manual tracing and FreeSurfer for estimating hippocampal volume over the adult lifespan. Hum. Brain Mapp. 39 2500–2513. 10.1002/HBM.24017 PubMed DOI PMC

Schmitz T. W., Nathan Spreng R. Alzheimer’s Disease Neuroimaging Initiative (2016). Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology. Nat. Commun. 7:13249. 10.1038/ncomms13249 PubMed DOI PMC

Schöberl F., Pradhan C., Irving S., Buerger K., Xiong G., Kugler G., et al. (2020). Real-space navigation testing differentiates between amyloid-positive and -negative aMCI. Neurology 94 e861–e873. 10.1212/wnl.0000000000008758 PubMed DOI

Sheardova K., Vyhnalek M., Nedelska Z., Laczo J., Andel R., Marciniak R., et al. (2019). Czech Brain Aging Study (CBAS): prospective multicentre cohort study on risk and protective factors for dementia in the Czech republic. BMJ Open 9:e030379. 10.1136/bmjopen-2019-030379 PubMed DOI PMC

Sheppard D. P., Graves L. V., Holden H. M., Delano-Wood L., Bondi M. W., Gilbert P. E. (2016). Spatial pattern separation differences in older adult carriers and non-carriers for the apolipoprotein E epsilon 4 allele. Neurobiol. Learn. Mem. 129 113–119. 10.1016/j.nlm.2015.04.011 PubMed DOI PMC

Spampinato M. V., Langdon B. R., Patrick K. E., Parker R. O., Collins H., Pravata’ E., et al. (2016). Gender, apolipoprotein E genotype, and mesial temporal atrophy: 2-year follow-up in patients with stable mild cognitive impairment and with progression from mild cognitive impairment to Alzheimer’s disease. Neuroradiology 58 1143–1151. 10.1007/s00234-016-1740-8 PubMed DOI

Stark S. M., Yassa M. A., Lacy J. W., Stark C. E. L. (2013). A task to assess behavioral pattern separation (BPS) in humans: data from healthy aging and mild cognitive impairment. Neuropsychologia 51 2442–2449. 10.1016/j.neuropsychologia.2012.12.014 PubMed DOI PMC

Teipel S. J., Flatz W., Ackl N., Grothe M., Kilimann I., Bokde A. L., et al. (2014). Brain atrophy in primary progressive aphasia involves the cholinergic basal forebrain and Ayala’s nucleus. Psychiatry Res. 221 187–194. 10.1016/J.PSCYCHRESNS.2013.10.003 PubMed DOI PMC

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 128 2626–2644. 10.1093/brain/awh589 PubMed DOI

Tustison N. J., Avants B. B., Cook P. A., Zheng Y., Egan A., Yushkevich P. A., et al. (2010). N4ITK: improved N3 bias correction. IEEE Trans. Med. Imaging 29 1310–1320. 10.1109/TMI.2010.2046908 PubMed DOI PMC

Vanderstichele H., Bibl M., Engelborghs S., Le Bastard N., Lewczuk P., Molinuevo J. L., et al. (2012). Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: a consensus paper from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement. 8 65–73. 10.1016/J.JALZ.2011.07.004 PubMed DOI

Velayudhan L., Proitsi P., Westman E., Muehlboeck J. S., Mecocci P., Vellas B., et al. (2013). Entorhinal cortex thickness predicts cognitive decline in Alzheimer’s disease. J. Alzheimers. Dis. 33 755–766. 10.3233/JAD-2012-121408 PubMed DOI

Webb C. E., Foster C. M., Horn M. M., Kennedy K. M., Rodrigue K. M. (2020). Beta-amyloid burden predicts poorer mnemonic discrimination in cognitively normal older adults. Neuroimage 221:117199. 10.1016/J.NEUROIMAGE.2020.117199 PubMed DOI PMC

Wolf D., Grothe M., Fischer F. U., Heinsen H., Kilimann I., Teipel S., et al. (2014). Association of basal forebrain volumes and cognition in normal aging. Neuropsychologia 53 54–63. 10.1016/J.NEUROPSYCHOLOGIA.2013.11.002 PubMed DOI

Yassa M. A., Mattfeld A. T., Stark S. M., Stark C. E. L. (2011b). Age-related memory deficits linked to circuit-specific disruptions in the hippocampus. Proc. Natl. Acad. Sci. U.S.A. 108 8873–8878. 10.1073/pnas.1101567108 PubMed DOI PMC

Yassa M. A., Lacy J. W., Stark S. M., Albert M. S., Gallagher M., Stark C. E. L. (2011a). Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults. Hippocampus 21 968–979. 10.1002/hipo.20808 PubMed DOI PMC

Yassa M. A., Stark C. E. L. (2011). Pattern separation in the hippocampus. Trends Neurosci. 34 515–525. 10.1016/j.tins.2011.06.006 PubMed DOI PMC

Yushkevich P. A., Piven J., Hazlett H. C., Smith R. G., Ho S., Gee J. C., et al. (2006). User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage 31 1116–1128. 10.1016/J.NEUROIMAGE.2006.01.015 PubMed DOI

Spatial navigation questionnaires as a supportive diagnostic tool in early Alzheimer's disease

Plasminogen activator inhibitor-1 serum levels in frontotemporal lobar degeneration

Different Profiles of Spatial Navigation Deficits In Alzheimer's Disease Biomarker-Positive Versus Biomarker-Negative Older Adults With Amnestic Mild Cognitive Impairment