Atrophy, hypometabolism and clinical trajectories in patients with amyloid-negative Alzheimer’s disease
Open accessAbstract
See O'Sullivan and Vann (doi:10.1093/aww166) for a scientific commentary on this article.About 15% of patients clinically diagnosed with Alzheimer's disease do not show high tracer retention on amyloid positon emission tomography imaging. The present study investigates clinical and demographic features, patterns of brain atrophy and hypometabolism and longitudinal clinical trajectories of these patients. Forty amyloid-negative patients carrying a pre-scan diagnosis of Alzheimer's disease dementia from four centres were included (11/29 females/males; mean age = 67 ± 9). Detailed clinical histories, including the clinical diagnoses before and after the amyloid scan and at follow-up, were collected. Patients were classified according to their pre-scan clinical phenotype as amnestic (memory predominant), non-amnestic (predominant language, visuospatial or frontal symptoms), or non-specific (diffuse cognitive deficits). Demographic, clinical, neuropsychological, magnetic resonance imaging and (18)F-fluorodeoxyglucose positon emission tomography data were compared to 27 amyloid-positive typical Alzheimer's disease cases (14/13 females/males; mean age = 71 ± 10) and 29 amyloid-negative controls (15/14 females/males; mean age = 69 ± 12) matched for age, gender and education. There were 21 amnestic, 12 non-amnestic, and seven non-specific amyloid-negative Alzheimer's disease cases. Amyloid-negative subgroups did not differ in age, gender or education. After the amyloid scan, clinicians altered the diagnosis in 68% of amyloid-negative patients including 48% of amnestic versus 94% of non-amnestic and non-specific cases. Amnestic amyloid-negative cases were most often reclassified as frontotemporal dementia, non-amnestic as frontotemporal dementia or corticobasal degeneration, and non-specific as dementia with Lewy bodies or unknown diagnosis. The longer-term clinical follow-up was consistent with the post-scan diagnosis in most cases (90%), including in amnestic amyloid-negative cases whose post-positon emission tomography diagnosis remained Alzheimer's disease. While the non-amnestic and non-specific amyloid-negative cases usually showed patterns of atrophy and hypometabolism suggestive of another degenerative disorder, the amnestic amyloid-negative cases had subtle atrophy and hypometabolism, restricted to the retrosplenial/posterior cingulate cortex. Patients with a negative amyloid positon emission tomography scan following an initial clinical diagnosis of Alzheimer's disease have heterogeneous clinical presentations and neuroimaging profiles; a majority showed a clinical progression that was consistent with a neurodegenerative condition. In contrast, in the subgroup of amnestic amyloid-negative cases, the clinical presentation and follow-up usually remained consistent with Alzheimer's disease. An alternative diagnosis was not made in about half of the amnestic amyloid-negative cases, highlighting the need for a clinical framework and terminology to define these patients, who may have underlying limbic-predominant, non-amyloid-related pathologies.
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Differences among (N) biomarkers may result in discordances.
“These differences may result in discordances [36,43,115,119,159].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [159]
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- Authors
- Chételat, G., Ossenkoppele, R., Villemagne, V. L., Perrotin, A., Landeau, B., Mézenge, F., Jagust, W. J., Dore, V., Miller, B. L., Egret, S., Seeley, W. W., van der Flier, W. M., La Joie, R., Ames, D., van Berckel, B. N. M., Scheltens, P., Barkhof, F., Rowe, C. C., Masters, C. L., de La Sayette, V., Bouwman, F., & Rabinovici, G. D.
- Affiliations
- Inserm (FR)
- University of California, San Francisco (US)
- Austin Hospital (AU)
- Lawrence Berkeley National Laboratory (US)
- The University of Melbourne (AU)
- Amsterdam Neuroscience (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Florey Institute of Neuroscience and Mental Health (AU)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-06-29
- Volume
- 139
- Issue
- 9
- Pages
- 2528-2539
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC6276935
- OpenAlex
- W2466322520
- Cited by
- 80
- References
- 56
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 5 · 2020: 6 · 2019: 9 · 2018: 14 · 2017: 11 · 2016: 1
- FWCI
- 10.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Alzheimer's Association (P50 AG023501, P01-AG1972403)
- American Health Assistance Foundation
- BrightFocus Foundation
- Agence Nationale de la Recherche
- Center for Translational Molecular Medicine (02N-101)
- Internationale Stichting Alzheimer Onderzoek (05512)
- Alzheimer Nederland
- Région Normandie
- Medical Research Council (MR/K022113/1)
- National Health and Medical Research Council (1071430)
- National Institute on Aging (AG1972403, R01AG045611, P01 AG1972403, AG023501, NIA P01 AG1972403, P01AG019724, P50AG023501)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- amyloid PET, brain atrophy, hypometabolism, clinical trajectories, amnestic Alzheimer's disease, frontotemporal dementia, corticobasal degeneration, dementia with Lewy bodies, 18F-FDG PET, clinical phenotype, differential diagnosis of dementia
- MeSH terms
- Aged, Alzheimer Disease, Amnesia, Atrophy, Female, Follow-Up Studies, Gyrus Cinguli, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Positron-Emission Tomography
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