Browsing by Author "Stern, Yaakov"

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    Plasma p‐tau181, p‐tau217, and other blood‐based Alzheimer's disease biomarkers in a multi‐ethnic, community study
    (Wiley, 2021) Brickman, Adam M.; Manly, Jennifer J.; Honig, Lawrence S.; Sanchez, Danurys; Reyes-Dumeyer, Dolly; Lantigua, Rafael A.; Lao, Patrick J.; Stern, Yaakov; Vonsattel, Jean Paul; Teich, Andrew F.; Airey, David C.; Proctor, Nicholas Kyle; Dage, Jeffrey L.; Mayeux, Richard; Neurology, School of Medicine
    Introduction: Blood-based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multi-ethnic community study of aging and dementia. Methods: We measured plasma amyloid beta (Aβ)40, Aβ42, total tau (t-tau), phosphorylated tau (p-tau)181, and p-tau217, and neurofilament light chain (NfL) in 113 autopsied participants (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD. Results: P-tau181, p-tau217, and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased p-tau217 and p-tau181 were associated with subsequent AD diagnosis. Discussion: Blood-based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi-ethnic, community-based studies.
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    Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease
    (Oxford University Press, 2021) Ewers, Michael; Luan, Ying; Frontzkowski, Lukas; Neitzel, Julia; Rubinski, Anna; Dichgans, Martin; Hassenstab, Jason; Gordon, Brian A.; Chhatwal, Jasmeer P.; Levin, Johannes; Schofield, Peter; Benzinger, Tammie L.S; Morris, John C.; Goate, Alison; Karch, Celeste M.; Fagan, Anne M.; McDade, Eric; Allegri, Ricardo; Berman, Sarah; Chui, Helena; Cruchaga, Carlos; Farlow, Marty; Graff-Radford, Neill; Jucker, Mathias; Lee, Jae-Hong; Martins, Ralph N.; Mori, Hiroshi; Perrin, Richard; Xiong, Chengjie; Rossor, Martin; Fox, Nick C.; O’Connor, Antoinette; Salloway, Stephen; Danek, Adrian; Buerger, Katharina; Bateman, Randall J.; Habeck, Christian; Stern, Yaakov; Franzmeier, Nicolai; Alzheimer’s Disease Neuroimaging Initiative; Dominantly Inherited Alzheimer Network; Neurology, School of Medicine
    Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer's disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer's disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease.