Contribution of mixed pathology to medial temporal lobe atrophy in Alzheimer's disease

Flores, Robin de; Wisse, Laura; Das, Sandhitsu R.; Xie, Lin; McMillan, Corey T.; Trojanowski, John Q.; Robinson, John; Grossman, Murray; Lee, Edward; Irwin, David J.; Yushkevich, Paul A.; Wolk, David A.

doi:10.1002/alz.12079

Cited by 62 publications

(79 citation statements)

References 48 publications

(126 reference statements)

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“…This cohort specificity could be due to the intrinsic differences in the characteristics of the samples, notably differences in age, disease severity, or inclusion criteria: the ADNI patients were older, less severely impaired, and included patients with more amnestic-predominant presentations than the UCSF participants. Converging evidence suggests that in older patients with pathology-proven Alzheimer's disease, MTL atrophy is related to both Alzheimer's disease tau pathology and frequently comorbid TDP-43 pathology, [82][83][84] an entity also known as limbic-predominant agerelated TDP-43 encephalopathy 85 and often associated with hippocampal sclerosis. In the older ADNI cohort, MTL degeneration could therefore stem not only from Alzheimer's disease neuropathology but also from comorbid TDP-43 or hippocampal sclerosis.…”

Section: Discussionmentioning

confidence: 99%

Glucose metabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease

Strom

Iaccarino

Edwards

et al. 2021

Preprint

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Posterior cortical hypometabolism measured with [18F]-Fluorodeoxyglucose (FDG)-PET is a well-known marker of Alzheimer′s disease-associated neurodegeneration, but its associations with underlying neuropathological processes are unclear. We assessed the relative contributions of three potential mechanisms causing hypometabolism in the retrosplenial and inferior parietal cortices: local molecular (amyloid and tau) pathology and atrophy, distant factors including contributions from the degenerating medial temporal lobe or molecular pathology in functionally connected regions, and the presence of the apolipoprotein E (APOE) ϵ4 allele. Two hundred and thirty-two amyloid-positive cognitively impaired patients from two independent cohorts (University of California, San Francisco, UCSF, and Alzheimer′s Disease Neuroimaging Initiative, ADNI) underwent MRI and PET with FDG, amyloid-PET using [11C]-Pittsburgh Compound B, [18F]-Florbetapir, or [18F]-Florbetaben, and [18F]-Flortaucipir tau-PET within one year. Standard uptake value ratios (SUVR) were calculated using tracer-specific reference regions. Brain regions were defined in native space using FreeSurfer. Regression analyses were run within cohorts to identify variables associated with retrosplenial or inferior parietal FDG SUVR. On average, ADNI patients were older and had less severe cognitive impairment than UCSF patients. Regional patterns of hypometabolism were similar between cohorts, though there were cohort differences in regional gray matter atrophy. Local cortical thickness and tau-PET (but not amyloid-PET) were independently associated with both retrosplenial and inferior parietal FDG SUVR (ΔR2 = .09 to .21) across cohorts in models that also included age and disease severity (local model). Including medial temporal lobe volume improved the retrosplenial FDG model in ADNI (ΔR2 = .04, p = .008) but not UCSF (ΔR2 < .01, p = .52), and did not improve the inferior parietal models (ΔR2s < .01, ps > .37). Interaction analyses revealed that medial temporal volume was more strongly associated with retrosplenial FDG SUVR at earlier disease stages (p = .06 in UCSF, p = .046 in ADNI). Models including molecular pathology in functionally connected regions, defined based on task-free functional MRI data from the Neurosynth database, or APOE ϵ4 did not outperform local models. Overall, hypometabolism in cognitively impaired patients primarily reflected local atrophy and tau pathology, with an added contribution of medial temporal lobe degeneration at earlier disease stages. Our data did not support hypotheses of a detrimental effect of pathology in connected regions or the presence of the APOE ϵ4 allele in impaired participants. FDG-PET reflects structural neurodegeneration and tau, but not amyloid, pathology at symptomatic stages of Alzheimer′s disease.

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Section: Discussionmentioning

confidence: 99%

Glucose metabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease

Strom

Iaccarino

Edwards

et al. 2021

Preprint

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“…Degeneration of the medial temporal lobe, a critical brain region involved in memory formation, is a well-known indicator for AD [ 11 , 12 , 13 ]. The medial temporal lobe system comprises the hippocampal region and the adjacent entorhinal, perirhinal, and parahippocampal cortices (reviewed in [ 14 ]).…”

Section: Introductionmentioning

confidence: 99%

Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aβ Plaques

Garad

Edelmann

Leßmann

2021

IJMS

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Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive and irreversible cognitive decline, with no disease-modifying therapy until today. Spike timing-dependent plasticity (STDP) is a Hebbian form of synaptic plasticity, and a strong candidate to underlie learning and memory at the single neuron level. Although several studies reported impaired long-term potentiation (LTP) in the hippocampus in AD mouse models, the impact of amyloid-β (Aβ) pathology on STDP in the hippocampus is not known. Using whole cell patch clamp recordings in CA1 pyramidal neurons of acute transversal hippocampal slices, we investigated timing-dependent (t-) LTP induced by STDP paradigms at Schaffer collateral (SC)-CA1 synapses in slices of 6-month-old adult APP/PS1 AD model mice. Our results show that t-LTP can be induced even in fully developed adult mice with different and even low repeat STDP paradigms. Further, adult APP/PS1 mice displayed intact t-LTP induced by 1 presynaptic EPSP paired with 4 postsynaptic APs (6× 1:4) or 1 presynaptic EPSP paired with 1 postsynaptic AP (100× 1:1) STDP paradigms when the position of Aβ plaques relative to recorded CA1 neurons in the slice were not considered. However, when Aβ plaques were live stained with the fluorescent dye methoxy-X04, we observed that in CA1 neurons with their somata <200 µm away from the border of the nearest Aβ plaque, t-LTP induced by 6× 1:4 stimulation was significantly impaired, while t-LTP was unaltered in CA1 neurons >200 µm away from plaques. Treatment of APP/PS1 mice with the anti-inflammatory drug fingolimod that we previously showed to alleviate synaptic deficits in this AD mouse model did not rescue the impaired t-LTP. Our data reveal that overexpression of APP and PS1 mutations in AD model mice disrupts t-LTP in an Aβ plaque distance-dependent manner, but cannot be improved by fingolimod (FTY720) that has been shown to rescue conventional LTP in CA1 of APP/PS1 mice.

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“…The right- and left-sided volumes and thicknesses were averaged for analyses. An anterior-to-posterior-hippocampal-volume ratio was also calculated, given prior work suggesting that this ratio may be associated with the presence of TDP-43 pathology ( de Flores et al, 2020 ). WMH volumes, which were downloaded from the ADNI website, were quantified via an automated detection method that utilized T1-, T2-, and proton-density weighted MRI images, as previously described ( Schwarz et al, 2009 , Dadar et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Oh brother, where art tau? Amyloid, neurodegeneration, and cognitive decline without elevated tau

McCollum

Das

Xie

et al. 2021

NeuroImage: Clinical

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Highlights Amyloid, tau and neurodegeneration are Alzheimer’s disease (AD) biomarkers. Mild cognitive impairment (MCI) cases were grouped using the “A/T/(N)” model. A+T-N+ MCI had less episodic memory loss and slower decline than A+T+N+ MCI. A+T-N+ MCI was more like A-T-N+ than A+T+N+ MCI on whole brain cortical thickness. A+T-N+ MCI’s less “AD-like” profile suggests that non-AD pathologies drive symptoms.

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Contribution of mixed pathology to medial temporal lobe atrophy in Alzheimer's disease

Cited by 62 publications

References 48 publications

Glucose metabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease

Glucose metabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease

Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aβ Plaques

Oh brother, where art tau? Amyloid, neurodegeneration, and cognitive decline without elevated tau

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