Cognitive complaints in older adults at risk for Alzheimer's disease are associated with altered resting‐state networks

Contreras, Joey A.; Goñi, Joaquín; Risacher, Shannon L.; Amico, Enrico; Yoder, Karmen K.; Džemidžić, Mario; West, John D.; McDonald, Brenna C.; Farlow, Martin R.; Sporns, Olaf; Saykin, Andrew J.

doi:10.1016/j.dadm.2016.12.004

Cited by 57 publications

(70 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, AD brains accumulate Aβ, tau, and a number of other proteins, suggesting the failure of shared protein turnover pathways 4,116 . However, pathogenesis of AD is now recognized as beginning well before obvious "pathology" can be detected [117][118][119] . In addition, the potential diseasemodifying activity of rivastigmine may be due not so much to reduction of Aβ but stimulation of neurotrophic sAPPα production and other effects of ADAM proteins.…”

Section: Discussionmentioning

confidence: 99%

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

et al. 2020

View full text Add to dashboard Cite

Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer's disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases-Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the nonamyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD.

show abstract

Section: Discussionmentioning

confidence: 99%

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

et al. 2020

View full text Add to dashboard Cite

show abstract

“…These results suggest that people can maintain good cognitive abilities and successful day-to-day functioning despite significant neuronal loss and atrophy. This disjunction between structure and function is a feature of healthy ageing, but we have shown that it also characterises presymptomatic FTD, over and [39] and dementia [38]. Here, we show the significance of the maintenance of this functional network organisation, with a progressively stronger correlation with cognitive performance as seemingly healthy adults approach the age of expected onset of FTD.…”

Section: Discussionmentioning

confidence: 50%

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Tsvetanov

Gazzina

Jones

et al. 2019

Preprint

View full text Add to dashboard Cite

INTRODUCTION: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial Frontotemporal dementia (FTD). METHODS: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. RESULTS: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviourally-relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. DISCUSSION: Our findings suggest that maintenance of functional network connectivity enables carriers to maintain cognitive performance.

show abstract

“… Zhang, et al 2016 [103] 76 aMCI, 19 ADD, 23 CNC RAVLT, MMSE, ADAS, Logical Memory I and II Functional connectivity between 18ROIs/Aβ PET, APOE ε4 status Medial frontal gyrus and parahippocampus functional connectivity negatively correlated with memory in aMCI and ADD. Contreras, et al 2017 [104] 21 aMCI, 8 ADD, 16 subjective cognitive decline, 13 CNC CVLT-II ICA (resting-state network, visual network, DMN and frontoparietal network) DMN and frontoparietal network connectivity positively correlated with recall. Abbreviations: APOE ε4, apolipoprotein E ε4; CNC, cognitively normal control; aMCI, amnestic mild cognitive impairment; MCI, mild cognitive impairment; naMCI, nonamnestic mild cognitive impairment; Aβ, amyloidβ; ADD, Alzheimer's disease dementia; RAVLT, Rey Auditory Verbal Learning Test; AVLT, Auditory Verbal Learning Test; RCFT, Rey Complex Figure Test; CVLT, California Verbal Learning Test; WMS, Wechsler Memory Scale; ADAS, Alzheimer's Disease Assessment Scales; MMSE, Mini–Mental State Examination; CERAD-WL, Consortium to Establish a Registry for Alzheimer's Disease-Word list; DMN, default mode network; ECN, executive control network; PCG, posterior cingulate gyrus; R, right; PFC, prefrontal cortex; VBM, voxel-based morphometry; L, left; PiB PET, Pittsburgh compound B positron emission tomography; ICA, independent component analysis; HC, hippocampus; DG, dentate gyrus; MTL, medial temporal lobe; HC, hippocampus; GM, gray matter; FDG-PET, fluorodeoxyglucose positron emission tomography; ROI, region of interest.…”

Section: Functional Mrimentioning

confidence: 99%

Current understanding of magnetic resonance imaging biomarkers and memory in Alzheimer's disease

Bayram

Caldwell

Banks

2018

A&D Transl Res & Clin Interv

View full text Add to dashboard Cite

Alzheimer's disease (AD) is caused by a cascade of changes to brain integrity. Neuroimaging biomarkers are important in diagnosis and monitoring the effects of interventions. As memory impairments are among the first symptoms of AD, the relationship between imaging findings and memory deficits is important in biomarker research. The most established magnetic resonance imaging (MRI) finding is hippocampal atrophy, which is related to memory decline and currently used as a diagnostic criterion for AD. While the medial temporal lobes are impacted early by the spread of neurofibrillary tangles, other networks and regional changes can be found quite early in the progression. Atrophy in several frontal and parietal regions, cortical thinning, and white matter alterations correlate with memory deficits in early AD. Changes in activation and connectivity have been detected by functional MRI (fMRI). Task-based fMRI studies have revealed medial temporal lobe hypoactivation, parietal hyperactivation, and frontal hyperactivation in AD during memory tasks, and activation patterns of these regions are also altered in preclinical and prodromal AD. Resting state fMRI has revealed alterations in default mode network activity related to memory in early AD. These studies are limited in part due to the historic inclusion of patients who had suspected AD but likely did not have the disorder. Modern biomarkers allow for more diagnostic certainty, allowing better understanding of neuroimaging markers in true AD, even in the preclinical stage. Larger patient cohorts, comparison of candidate imaging biomarkers to more established biomarkers, and inclusion of more detailed neuropsychological batteries to assess multiple aspects of memory are needed to better understand the memory deficit in AD and help develop new biomarkers. This article reviews MRI findings related to episodic memory impairments in AD and introduces a new study with multimodal imaging and comprehensive neuropsychiatric evaluation to overcome current limitations.

show abstract

Cognitive complaints in older adults at risk for Alzheimer's disease are associated with altered resting‐state networks

Cited by 57 publications

References 49 publications

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Current understanding of magnetic resonance imaging biomarkers and memory in Alzheimer's disease

Contact Info

Product

Resources

About