Differential diagnosis of amnestic dementia patients based on an FDG‐PET signature of autopsy‐confirmed LATE‐NC

Grothe, Michel J.; Moscoso, Alexis; Silva‐Rodríguez, Jesús; Lange, Catharina; Nho, Kwangsik; Saykin, Andrew J.; Nelson, Peter T.; Schöll, Michael; Buchert, Ralph; Teipel, Stefan J.

doi:10.1002/alz.12763

Cited by 25 publications

(24 citation statements)

References 49 publications

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“…4,27 Our results can serve as foundation for larger studies to define volumetric ranges in individuals with HS and AD, and to explore if HS-associated volume changes are observed at pre-dementia stages. These early volumetric differences could be combined with recently described fluorodeoxyglucose-positron emission tomography (FDG-PET) medial-temporal hypometabolic changes in HS 48 and TDP-43, 49,50 to reinforce the distinction of these pathologies from AD.…”

Section: Discussionmentioning

confidence: 96%

Hippocampal sclerosis of aging at post‐mortem is evident on MRI more than a decade prior

Ortega-Cruz

Iglesias

Rábano

et al. 2023

Alzheimer's & Dementia

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IntroductionHippocampal sclerosis of aging (HS) is an important component of combined dementia neuropathology. However, the temporal evolution of its histologically‐defined features is unknown. We investigated pre‐mortem longitudinal hippocampal atrophy associated with HS, as well as with other dementia‐associated pathologies.MethodsWe analyzed hippocampal volumes from magnetic resonance imaging (MRI) segmentations in 64 dementia patients with longitudinal MRI follow‐up and post‐mortem neuropathological evaluation, including HS assessment in the hippocampal head and body.ResultsSignificant HS‐associated hippocampal volume changes were observed throughout the evaluated timespan, up to 11.75 years before death. These changes were independent of age and Alzheimer's disease (AD) neuropathology and were driven specifically by CA1 and subiculum atrophy. AD pathology, but not HS, was associated significantly with the rate of hippocampal atrophy.DiscussionHS‐associated volume changes are detectable on MRI earlier than 10 years before death. Based on these findings, volumetric cutoffs could be derived for in vivo differentiation between HS and AD.HIGHLIGHTS Hippocampal atrophy was found in HS+ patients earlier than 10 years before death. These early pre‐mortem changes were driven by reduced CA1 and subiculum volumes. Rates of hippocampus and subfield volume decline were independent of HS. In contrast, steeper atrophy rates were associated with AD pathology burden. Differentiation between AD and HS could be facilitated based on these MRI findings.

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Section: Discussionmentioning

confidence: 96%

Hippocampal sclerosis of aging at post‐mortem is evident on MRI more than a decade prior

Ortega-Cruz

Iglesias

Rábano

et al. 2023

Alzheimer's & Dementia

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“…Similarly, medial temporal hypometabolism on FDG-PET was recently suggested as a biomarker of LATE, based on both autopsy-validated and a large cross-sectional FDG data set. 25 Increasing evidence suggests that medial temporal atrophy and dysfunction occurring in the absence of Aβ 26 or tau 27 pathology are associated with cognitive decline. Further work should better determine the sensitivity of different tau-PET tracers to PART to better distinguish the respective contributions of PART and LATE to hippocampal atrophy and cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults

Hanseeuw,

Jacobs,

Schultz

et al. 2023

Neurology

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Background:Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared to amyloid-beta (Aβ) and tau imaging, it is less specific for Alzheimer’s disease (AD) pathology. This lack of specificity could provide indirect information about potential co-pathologies that cannot be observedin vivo. In this prospective cohort study, we aimed to assess the associations among Aβ, tau, HV, and cognition, measured over a ten-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aβ and tau.Methods:We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI [follow-up duration: 1.3-7.0y], neocortical Aβ imaging on PiB PET scans [1.9-8.5y], entorhinal and inferior temporal tau on Flortaucipir PET scans [0.8-6.0y], and the Preclinical Alzheimer Cognitive Composite [3.0-9.8y] were prospectively collected. We evaluated the longitudinal associations between Aβ, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline.Results:We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years old (range: 63-87). Thirty-four participants (27%) exhibited an initial high-Aβ burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2=0.28, p<0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aβ and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers.Discussion:In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aβ or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwisein vivo.

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“…The 18 F-Fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) is a functional biomarker of neurodegeneration that has illuminated patterns of hypometabolism suggestive of LATE. [61][62][63] By assessing the hypometabolism of the MTL and frontal supraorbital gyrus (FSO) relative to the metabolic sparing of the inferior temporal gyrus (I), the I/MTL/FSO ratio has roughly 80% sensitivity and specificity in distinguishing cases along the AD continuum with and without comorbid LATE. 63 Further, the ratio of I/MTL was able to identify subgroups of patients who were tau-negative (T-) and either amyloid-positive (A+) or negative (A-) on PET.…”

Section: Positron Emission Tomographymentioning

confidence: 99%

When Alzheimer's isLATE: Why Does it Matter?

Nelson

Schneider

Jicha

et al. 2023

Annals of Neurology

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Recent therapeutic advances provide heightened motivation for accurate diagnosis of the underlying biologic causes of dementia. This review focuses on the importance of clinical recognition of limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). LATE affects approximately one‐quarter of older adults and produces an amnestic syndrome that is commonly mistaken for Alzheimer's disease (AD). Although AD and LATE often co‐occur in the same patients, these diseases differ in the protein aggregates driving neuropathology (Aβ amyloid/tau vs TDP‐43). This review discusses signs and symptoms, relevant diagnostic testing, and potential treatment implications for LATE that may be helpful for physicians, patients, and families. ANN NEUROL 2023;94:211–222

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Differential diagnosis of amnestic dementia patients based on an FDG‐PET signature of autopsy‐confirmed LATE‐NC

Cited by 25 publications

References 49 publications

Hippocampal sclerosis of aging at post‐mortem is evident on MRI more than a decade prior

Hippocampal sclerosis of aging at post‐mortem is evident on MRI more than a decade prior

Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults

When Alzheimer's isLATE: Why Does it Matter?

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