A biomarker study in long-lasting amnestic mild cognitive impairment

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Abstract

Background

Mild cognitive impairment (MCI) is a heterogeneous syndrome resulting from Alzheimer’s disease (AD) as well as to non-AD and non-neurodegenerative conditions. A subset of patients with amnestic MCI (aMCI) present with an unusually long-lasting course, a slow rate of clinical neuropsychological progression, and evidence of focal involvement of medial temporal lobe structures. In the present study, we explored positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in a sample of subjects with aMCI with such clinical features in order to provide in vivo evidence to improve disease characterisation in this subgroup.

Methods

Thirty consecutive subjects with aMCI who had long-lasting memory impairment (more than 4 years from symptom onset) and a very slow rate of cognitive progression were included. All subjects underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) metabolic imaging. A measure of cerebral amyloid load, by PET and/or CSF, was obtained in 26 of 30 subjects. The mean clinical follow-up was 58.3 ± 10.1 months.

Results

No patient progressed to dementia during the follow-up. The typical AD FDG-PET pattern of temporoparietal hypometabolism was not present in any of the subjects. In contrast, a selective medial temporal lobe hypometabolism was present in all subjects, with an extension to frontolimbic regions in some subjects. PET imaging showed absent or low amyloid load in the majority of samples. The values were well below those reported in prodromal AD, and they were slightly elevated in only two subjects, consistent with the CSF β-amyloid (1–42) protein values. Notably, no amyloid load was present in the hippocampal structures.

Conclusions

FDG-PET and amyloid-PET together with CSF findings questioned AD pathology as a unique neuropathological substrate in this aMCI subgroup with long-lasting disease course. The possibility of alternative pathological conditions, such as argyrophilic grain disease, primary age-related tauopathy or age-related TDP-43 proteinopathy, known to spread throughout the medial temporal lobe and limbic system structures should be considered in these patients with MCI.

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Most cited references 32

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Primary age-related tauopathy (PART): a common pathology associated with human aging.

John F Crary, John Q Trojanowski, Julie A Schneider … (2014)

We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

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Neuroimaging correlates of pathologically defined subtypes of Alzheimer's disease: a case-control study.

Jennifer L. Whitwell, Dennis W. Dickson, Melissa Murray … (2012)

Three subtypes of Alzheimer's disease (AD) have been pathologically defined on the basis of the distribution of neurofibrillary tangles: typical AD, hippocampal-sparing AD, and limbic-predominant AD. Compared with typical AD, hippocampal-sparing AD has more neurofibrillary tangles in the cortex and fewer in the hippocampus, whereas the opposite pattern is seen in limbic-predominant AD. We aimed to determine whether MRI patterns of atrophy differ between these subtypes and whether structural neuroimaging could be a useful predictor of pathological subtype at autopsy. We identified patients who had been followed up in the Mayo Clinic Alzheimer's Disease Research Center (Rochester, MN, USA) or in the Alzheimer's Disease Patient Registry (Rochester, MN, USA) between 1992 and 2005. To be eligible for inclusion, participants had to have had dementia, AD pathology at autopsy (Braak stage ≥IV and intermediate to high probability of AD), and an ante-mortem MRI. Cases were assigned to one of three pathological subtypes--hippocampal-sparing, limbic-predominant, and typical AD--on the basis of neurofibrillary tangle counts in hippocampus and cortex and ratio of hippocampal to cortical burden, without reference to neuronal loss. Voxel-based morphometry and atlas-based parcellation were used to compare patterns of grey matter loss between groups and with age-matched control individuals. Neuroimaging was obtained at the time of first presentation. To summarise pair-wise group differences, we report the area under the receiver operator characteristic curve (AUROC). Of 177 eligible patients, 125 (71%) were classified as having typical AD, 33 (19%) as having limbic-predominant AD, and 19 (11%) as having hippocampal-sparing AD. Most patients with typical (98 [78%]) and limbic-predominant AD (31 [94%]) initially presented with an amnestic syndrome, but fewer patients with hippocampal-sparing AD (eight [42%]) did. The most severe medial temporal atrophy was recorded in patients with limbic-predominant AD, followed by those with typical disease, and then those with hippocampal-sparing AD. Conversely, the most severe cortical atrophy was noted in patients with hippocampal-sparing AD, followed by those with typical disease, and then limbic-predominant AD. The ratio of hippocampal to cortical volumes allowed the best discrimination between subtypes (p<0·0001; three-way AUROC 0·52 [95% CI 0·47-0·52]; ratio of AUROC to chance classification 3·1 [2·8-3·1]). Patients with typical AD and non-amnesic initial presentation had a significantly higher ratio of hippocampal to cortical volumes (median 0·045 [IQR 0·035-0·056]) than did those with an amnesic presentation (0·041 [0·031-0·057]; p=0·001). Patterns of atrophy on MRI differ across the pathological subtypes of AD. MRI regional volumetric analysis can reliably track the distribution of neurofibrillary tangle pathology and can predict pathological subtype of AD at autopsy. US National Institutes of Health (National Institute on Aging). Copyright © 2012 Elsevier Ltd. All rights reserved.

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Amnestic syndrome of the medial temporal type identifies prodromal AD: a longitudinal study.

M Sarazin, M Volteau, B Dubois … (2007)

To compare the power of tests assessing different cognitive domains for the identification of prodromal Alzheimer disease (AD) among patients with mild cognitive impairment (MCI). Given the early involvement of the medial temporal lobe, a precocious and specific pattern of memory disorders might be expected for the identification of prodromal AD. A total of 251 patients with MCI were tested at baseline by a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for verbal episodic memory; the Benton Visual Retention Test for visual memory; the Deno 100 and verbal fluency for language; a serial digit learning test and the double task of Baddeley for working memory; Wechsler Adult Intelligence Scale (WAIS) similarities for conceptual elaboration; and the Stroop test, the Trail Making test, and the WAIS digit symbol test for executive functions. The patients were followed at 6-month intervals for up to 3 years in order to identify those who converted to AD vs those who remained stable over time. Statistical analyses were based on receiver operating characteristic curve and Cox proportional hazards models. A total of 59 subjects converted to AD dementia. The most sensitive and specific test for diagnosis of prodromal AD was the FCSRT. Significant cutoff for the diagnosis was 17/48 for free recall, 40/48 for total recall, and below 71% for index of sensitivity of cueing (% of efficacy of semantic cues for retrieval). The amnestic syndrome of the medial temporal type, defined by the Free and Cued Selective Recall Reminding Test, is able to distinguish patients at an early stage of Alzheimer disease from mild cognitive impairment non-converters.

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Author and article information

Contributors

Chiara Cerami: +39 02 26435760 , cerami.chiara@hsr.it

Alessandra Dodich: dodich.alessandra@hsr.it

Sandro Iannaccone: iannaccone.sandro@hsr.it

Giuseppe Magnani: magnani.giuseppe@hsr.it

Roberto Santangelo: santangelo.roberto@hsr.it

Luca Presotto: presotto.luca@hsr.it

Alessandra Marcone: marcone.alessandra@hsr.it

Luigi Gianolli: gianolli.luigi@hsr.it

Stefano F. Cappa: cappa.stefano@hsr.it

Daniela Perani: perani.daniela@hsr.it

Journal

Journal ID (nlm-ta): Alzheimers Res Ther

Journal ID (iso-abbrev): Alzheimers Res Ther

Title: Alzheimer's Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1758-9193

Publication date (Electronic): 25 April 2018

Publication date PMC-release: 25 April 2018

Publication date Collection: 2018

Volume: 10

Electronic Location Identifier: 42

Affiliations

[1 ]ISNI 0000000417581884, GRID grid.18887.3e, Division of Neuroscience, San Raffaele Scientific Institute, ; Milan, Italy

[2 ]Clinical Neuroscience Department, San Raffaele Turro Hospital, Milan, Italy

[3 ]ISNI 0000000417581884, GRID grid.18887.3e, Neurology Department, , San Raffaele Hospital, ; Milan, Italy

[4 ]ISNI 0000000417581884, GRID grid.18887.3e, Nuclear Medicine Department, , San Raffaele Hospital, ; Milan, Italy

[5 ]ISNI 0000 0001 0724 054X, GRID grid.30420.35, NeTS Center, , Istituto Universitario di Studi Superiori, ; Pavia, Italy

[6 ]GRID grid.419422.8, IRCCS S. Giovanni di Dio Fatebenefratelli, ; Brescia, Italy

[7 ]GRID grid.15496.3f, Università Vita-Salute San Raffaele, ; Milan, Italy

Article

Publisher ID: 369

DOI: 10.1186/s13195-018-0369-8

PMC ID: 5918759

PubMed ID: 29695292

SO-VID: ce5f2b81-6edb-4368-973b-ca76a75f7342

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 24 July 2017

Date accepted : 19 March 2018

Funding

Funded by: Eli-Lilly Grant 2011

Funded by: EU FP7 INMIND Project (FP7-HEALTH-2011)

Award ID: 278850

Funded by: CTN01_00177_165430 Project

Award ID: IVASCOMAR COD CUP B88F13000420008

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: positron emission tomography,mild cognitive impairment,alzheimer’s disease,medial temporal lobe dysfunction,fdg-pet,amyloid-pet

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ScienceOpen disciplines: Neurology

Keywords: positron emission tomography, mild cognitive impairment, alzheimer’s disease, medial temporal lobe dysfunction, fdg-pet, amyloid-pet

A biomarker study in long-lasting amnestic mild cognitive impairment

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Abstract

Background

Methods

Results

Conclusions

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Karger: Neurology and Neuroscience

Most cited references 32

Primary age-related tauopathy (PART): a common pathology associated with human aging.

Neuroimaging correlates of pathologically defined subtypes of Alzheimer's disease: a case-control study.

Amnestic syndrome of the medial temporal type identifies prodromal AD: a longitudinal study.

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