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. 2020 Aug 5;12(1):93.
doi: 10.1186/s13195-020-00647-w.

Neurodegenerative changes in early- and late-onset cognitive impairment with and without brain amyloidosis

Eddie C Stage Jr  1 , Diana Svaldi  1   2 , Meredith Phillips  3 , Victor Hugo Canela  1 , Tugce Duran  4 , Naira Goukasian  5 , Shannon L Risacher  6 , Andrew J Saykin  6   7   8 , Liana G Apostolova  9   10   11   12 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Neurodegenerative changes in early- and late-onset cognitive impairment with and without brain amyloidosis

Eddie C Stage Jr et al. Alzheimers Res Ther. .

Abstract

Background: A substantial number of patients clinically diagnosed with Alzheimer's disease do not harbor amyloid pathology. We analyzed the presence and extent of tau deposition and neurodegeneration in amyloid-positive (AD) and amyloid-negative (nonAD) ADNI subjects while also taking into account age of onset (< or > 65 years) as we expected that the emerging patterns could vary by age and presence or absence of brain amyloidosis.

Methods: One hundred and ten early-onset AD (EOAD), 121 EOnonAD, 364 late-onset AD (LOAD), and 175 LOnonAD mild cognitive impairment (MCI) and dementia (DEM) subjects were compared to 291 ADNI amyloid-negative control subjects using voxel-wise regression in SPM12 with cluster-level family-wise error correction at pFWE < 0.05). A subset of these subjects also received 18F-flortaucipir scans and allowed for analysis of global tau burden.

Results: As expected, relative to LOAD, EOAD subjects showed more extensive neurodegeneration and tau deposition in AD-relevant regions. EOnonADMCI showed no significant neurodegeneration, while EOnonADDEM showed bilateral medial and lateral temporal, and temporoparietal hypometabolism. LOnonADMCI and LOnonADDEM showed diffuse brain atrophy and a fronto-temporo-parietal hypometabolic pattern. LOnonAD and EOnonAD subjects failed to show significant tau binding.

Conclusions: LOnonAD subjects show a fronto-temporal neurodegenerative pattern in the absence of tau binding, which may represent underlying hippocampal sclerosis with TDP-43, also known as limbic-predominant age-related TDP-43 encephalopathy (LATE). The hypometabolic pattern observed in EOnonADDEM seems similar to the one observed in EOADMCI. Further investigation into the underlying etiology of EOnonAD is warranted.

Keywords: AD; Alzheimer’s disease; Early onset; Hippocampal sclerosis; LATE; Late onset; Limbic-predominant age-related TDP-43 encephalopathy; MRI; Neurodegeneration; PET; Tau.

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Conflict of interest statement

Eddie Stage, PhD, reports no competing interests.

Meredith Phillips, MS, reports no competing interests.

Victor Hugo Canela, MS, reports no competing interests.

Tugce Duran, BS, reports no competing interests.

Naira Goukasian, BS, reports no competing interests.

Shannon L. Risacher, PhD, reports no competing interests.

Andrew J. Saykin, PsyD, has received research support from Eli Lilly and AVID Radiopharmaceuticals.

Liana G. Apostolova, MD, MS, has served on an Advisory Board for Eli Lilly and Biogen and on the Speakers Bureau for Piramal and Eli Lilly.

Figures

Fig. 1
Fig. 1
MRI (top), FDG PET (middle), and tau PET (bottom) comparisons between the AD groups and CN. The significance maps show p < 0.05 thresholded FWE cluster-level corrected results of EOADMCI (N = 60), EOADDEM (N = 50), LOADMCI (N = 216), and LOADDEM (N = 148) vs. CN (N = 291). The results displayed here are for all subjects with available scans in each modality
Fig. 2
Fig. 2
MRI (top), FDG PET (middle), and tau PET (bottom) comparisons between the nonAD groups and CN. The significance maps show p < 0.05 thresholded FWE cluster-level corrected results of EOnonADMCI (N = 113), EOnonADDEM (N = 8), LOnonADMCI (N = 151), and LOnonADDEM (N = 24) vs. CN (N = 291). The results displayed here are for all subjects with available scans in each modality
See this image and copyright information in PMC

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