FDG‐PET markers of heterogeneity and different risk of progression in amnestic MCI

Caminiti, Silvia Paola; Francesco, Silvia De; Tondo, Giacomo; Galli, Alice; Redolfi, Alberto; Perani, Daniela

doi:10.1002/alz.13385

Cited by 9 publications

(12 citation statements)

References 75 publications

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“… 2 These findings underline the key role of the combination of brain metabolism and tau biomarkers for diagnosis and prognosis in aMCI. The present classification of individual FDG‐PET patterns in prodromal aMCI confirms the existence of distinct hypometabolic subtypes, as previously shown in another aMCI cohort using FDG PET 12 or in AD dementia series using FDG‐PET 4 and MRI. 3 However, there is still an ambiguous interpretation and consequent classification of the limbic‐predominant pattern within the AD spectrum.…”

Section: Discussionsupporting

confidence: 88%

“…We applied strict inclusion criteria for our sample: (i) aMCI diagnosis according to Petersen criteria 1 ; (ii) Mini‐Mental State Examination (MMSE), (iii) an FDG‐PET scan performed at baseline and analyzed using the optimized SPM procedure 13 showing brain hypometabolism in the typical AD‐like structures, namely the hippocampal structures and/or the temporoparietal associative cortex 12 (iv) a tau‐PET scan and (v) a structural MRI, both within a year from FDG‐PET. Thus, subjects with completely negative FDG‐PET scans or non‐AD FDG‐PET hypometabolic features were excluded.…”

Section: Methodsmentioning

confidence: 99%

“…Classification of FDG‐PET subtypes was performed according to a procedure recently validated in another large sample of aMCI. 12 Briefly, the procedure consists of a three‐step classification algorithm that combines information from the typical AD‐like and limbic‐like patterns and related hallmark regions (HR). The patterns and HRs were constructed using the automated anatomical labelling atlas (AAL) of functional anatomical regions.…”

Section: Methodsmentioning

confidence: 99%

“…This study aims to capture the possible brain metabolic heterogeneity during the aMCI prodromal phase by applying a data‐driven algorithm based on FDG‐PET 12 to define hypometabolism‐based subtypes in clinically comparable aMCI subjects, and subsequently compare them in terms of tau and amyloid biomarkers assessed by PET, and clinical follow‐up. This classification could usefully inform subject selection in disease‐modifying treatments.…”

Section: Introductionmentioning

confidence: 99%

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The diagnostic and prognostic value of tau‐PET in amnestic MCI with different FDG‐PET subtypes

Boccalini,

Caminiti,

Chiti

et al. 2024

Ann Clin Transl Neurol

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ObjectivesMild cognitive impairment presenting with an amnestic syndrome (aMCI) and amyloid positivity is considered due to AD. Many subjects, however, can show an overall very slow progression relevant for differential diagnosis, prognosis, and treatment. This study assessed PET biomarkers, including brain glucose metabolism, tau, and amyloid load, in a series of comparable aMCI at baseline, clinically evaluated at follow‐up.MethodsWe included 72 aMCI subjects from Geneva Memory Center (N = 31) and ADNI cohorts (N = 41), selected based on available FDG‐PET, tau‐PET, amyloid‐PET, and clinical follow‐up (2.3 years ± 1.2). A data‐driven algorithm classified brain metabolic patterns into subtypes that were then compared for clinical and PET biomarker measures and cognitive decline. Voxel‐wise comparisons were performed both with FDG‐PET and tau‐PET data.ResultsThe algorithm classified three metabolic subtypes, namely “Hippocampal‐sparing with cortical hypometabolism” (Type1; N = 27), “Hippocampal and cortical hypometabolism” (Type 2; N = 23), and “Medial temporal hypometabolism” (Type 3; N = 22). Amyloid positivity and tau accumulation in the medial temporal and neocortical regions characterized Type 1 and Type 2, whereas Type 3 showed no significant tau pathology, variable amyloid positivity, and stability at follow‐up. All tau‐positive patients, independently of the FDG‐based subtype, showed faster cognitive decline.InterpretationaMCI subjects can differ in metabolic patterns, tau and amyloid pathology, and clinical progression. Here, we complemented with PET tau biomarker the specific brain hypometabolic patterns at the individual level in the prodromal phase, contributing to the patient's classification. Tau PET is the most accurate biomarker in supporting or excluding the AD diagnosis in aMCI across metabolic subtypes and also predicting the risk of decline.

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Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The diagnostic and prognostic value of tau‐PET in amnestic MCI with different FDG‐PET subtypes

Boccalini,

Caminiti,

Chiti

et al. 2024

Ann Clin Transl Neurol

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“…A positive amyloid-PET scan should prompt further workup to assess the presence of neocortical tau pathology. The specification of “neocortical” tau as opposed to tau in general is to account for the limbic variant of Alzheimer’s disease wherein associated clinical and pathologic findings localize to the limbic system(67,68). Therefore, limbic Alzheimer’s disease, although less common than LATE-NC, qualifies for LANS.…”

Section: Methodsmentioning

confidence: 99%

A limbic-predominant amnestic neurodegenerative syndrome associated with TDP-43 pathology

Corriveau-Lecavalier,

Botha,

Graff-Radford

et al. 2023

Preprint

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Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neuropathologically-defined disease that affects 40% of persons in advanced age, but its associated neurological syndrome is not defined. LATE neuropathological changes (LATE-NC) are frequently comorbid with Alzheimer’s disease neuropathologic changes (ADNC). When seen in isolation, LATE-NC have been associated with a predominantly amnestic profile and slow clinical progression. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome (LANS) that is highly associated with LATE-NC but also other pathologic entities. The LANS criteria incorporate core, standard and advanced features that are measurablein vivo, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degenerative patterns and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate, low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic (n = 922) and ADNI (n = 93) cohorts and applied the LANS criteria to those with an antemortem predominant amnestic syndrome (Mayo,n= 165; ADNI,n= 53). ADNC, ADNC/LATE-NC and LATE-NC accounted for 35%, 37% and 4% of cases in the Mayo cohort, respectively, and 30%, 22%, and 9% of cases in the ADNI cohort, respectively. The LANS criteria effectively categorized these cases, with ADNC having the lowest LANS likelihoods, LATE-NC patients having the highest likelihoods, and ADNC/LATE-NC patients having intermediate likelihoods. A logistic regression model using the LANS features as predictors of LATE-NC achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in the ADNI cohort achieved a balanced accuracy of 73.3%. Patients with high LANS likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying ADNC/LATE-NC patients from the Mayo cohort according to their LANS likelihood revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of cognitive decline, and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of cognitive decline. The implementation of LANS criteria has implications to disambiguate the different driving etiologies of progressive amnestic presentations in older age and guide prognosis, treatment, and clinical trials. The development ofin vivobiomarkers specific to TDP-43 pathology are needed to refine molecular associations between LANS and LATE-NC and precise antemortem diagnoses of LATE.

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Retrosplenial hypometabolism precedes the conversion from mild cognitive impairment to Alzheimer's disease

Terstege,

Galea,

Epp

2024

Alzheimer's & Dementia

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INTRODUCTIONNot all individuals who experience mild cognitive impairment (MCI) transition through progressive stages of cognitive decline at the same rate, if at all. Previous observational studies have identified the retrosplenial cortex (RSC) as an early site of hypometabolism in MCI which seems to be predictive of later transition to Alzheimer's disease (AD).METHODSWe examined N = 399 MCI subjects with baseline 18F‐fluorodeoxyglucose positron emission tomography. Subjects were classified based on whether their diagnosis converted from MCI to AD.RESULTSWhole‐brain metabolism was decreased in converters (MCI‐AD). This effect was more prominent at the RSC, where MCI‐AD subjects showed even greater hypometabolism. Observations of RSC hypometabolism and its utility in predicting transition from MCI‐AD withstood statistical analyses in a large retrospective study.DISCUSSIONThese results point to the utility of incorporating RSC hypometabolism into predictive models of AD progression risk and call for further examination of mechanisms underlying this relationship.Highlights Not all individuals who develop MCI will progress to AD. Individuals with MCI who progress to AD show early whole‐brain hypometabolism. Early hypometabolism is particularly prominent at the RSC.

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FDG‐PET markers of heterogeneity and different risk of progression in amnestic MCI

Cited by 9 publications

References 75 publications

The diagnostic and prognostic value of tau‐PET in amnestic MCI with different FDG‐PET subtypes

The diagnostic and prognostic value of tau‐PET in amnestic MCI with different FDG‐PET subtypes

A limbic-predominant amnestic neurodegenerative syndrome associated with TDP-43 pathology

Retrosplenial hypometabolism precedes the conversion from mild cognitive impairment to Alzheimer's disease

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