Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

Jack, Clifford R.; Knopman, David S.; Jagust, William J.; Petersen, Ronald C.; Weiner, Michael W.; Aisen, Paul S.; Shaw, Leslie M.; Vemuri, Prashanthi; Wiste, Heather J.; Weigand, Stephen D.; Lesnick, Timothy G.; Pankratz, V. Shane; Donohue, Michael C.; Trojanowski, John Q.

doi:10.1016/s1474-4422(12)70291-0

Cited by 3,430 publications

(3,038 citation statements)

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“…When we compared levels with other AD biomarkers, we similarly observed no association between Ng and CSF Aβ 42 levels. This is perhaps not surprising, since amyloid deposition probably occurs many years before synaptic loss and neurodegeneration,30 and previous studies have shown no correlation between synaptic loss and amyloid plaque burden. In keeping with other studies,7 we did however find T‐tau and Ng levels to be strongly associated (which would also be in keeping with reports of lower levels of CSF T‐tau in PCA compared to other AD phenotypes31, 32), and a relationship – albeit not as strongly – between Ng and NFL.…”

Section: Discussionmentioning

confidence: 89%

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Wellington¹,

Paterson

Suárez‐González

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo assess whether high levels of cerebrospinal fluid neurogranin are found in atypical as well as typical Alzheimer's disease.MethodsImmunoassays were used to measure cerebrospinal fluid neurogranin in 114 participants including healthy controls (n = 27), biomarker‐proven amnestic Alzheimer's disease (n = 68), and the atypical visual variant of Alzheimer's (n = 19) according to international criteria. CSF total‐tau, Aβ42, and neurofilament light concentrations were investigated using commercially available assays. All affected individuals had T1‐weighted volumetric MR images available for analysis of whole and regional brain volumes. Associations between neurogranin, brain volumes, total‐tau, Aβ42, and neurofilament light were assessed.ResultsMedian cerebrospinal fluid neurogranin concentrations were higher in typical and atypical Alzheimer's compared to controls (P < 0.001 and P = 0.005). Both neurogranin and total‐tau concentrations, but not neurofilament light and Aβ42, were higher in typical Alzheimer's compared to atypical patients (P = 0.004 and P = 0.03). There were significant differences in the left hippocampus and right and left superior parietal lobules in atypical patients, which were larger (P = 0.03) and smaller (P = 0.001 and P < 0.001), respectively, compared to typical patients. We found no evidence of associations between neurogranin and brain volumes but a strong association with total‐tau (P < 0.001) and a weaker association with neurofilament light (P = 0.005).InterpretationThese results show significant differences in neurogranin and total‐tau between typical and atypical patients, which may relate to factors other than disease topography. The differential relationships between neurogranin, total‐tau and neurofilament light in the Alzheimer's variants, provide evidence for mechanistically distinct and coupled markers of neurodegeneration.

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Section: Discussionmentioning

confidence: 89%

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Wellington¹,

Paterson

Suárez‐González

et al. 2018

Ann Clin Transl Neurol

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“…This stage of milder cognitive problems, accompanied by localized changes in brain metabolism and functioning (Jack et al., 2010, 2013), provides an opportunity for treatment (Cummings & Zhong, 2014; Hampel et al., 2010). Biomarkers related to disease progression in these early stages are essential for proper quantitative evaluation.…”

Section: Introductionmentioning

confidence: 99%

“…Biomarkers related to disease progression in these early stages are essential for proper quantitative evaluation. If EC detects AD‐related network alterations in the presymptomatic stage of the disease or in people with a well‐defined risk for AD, this will further increase opportunities for treatment development (Cummings & Zhong, 2014; Jack et al., 2013). …”

Section: Introductionmentioning

confidence: 99%

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

et al. 2018

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IntroductionAmyloid plaque deposition in the brain is an early pathological change in Alzheimer's disease (AD), causing disrupted synaptic connections. Brain network disruptions in AD have been demonstrated with eigenvector centrality (EC), a measure that identifies central regions within networks. Carrying an apolipoprotein (APOE)‐ε4 allele is a genetic risk for AD, associated with increased amyloid deposition. We studied whether APOE‐ε4 carriership is associated with EC disruptions in cognitively normal individuals.MethodsA total of 261 healthy middle‐aged to older adults (mean age 56.6 years) were divided into high‐risk (APOE‐ε4 carriers) and low‐risk (noncarriers) groups. EC was computed from resting‐state functional MRI data. Clusters of between‐group differences were assessed with a permutation‐based method. Correlations between cluster mean EC with brain volume, CSF biomarkers, and psychological test scores were assessed.ResultsDecreased EC in the visual cortex was associated with APOE‐ε4 carriership, a genetic risk factor for AD. EC differences were correlated with age, CSF amyloid levels, and scores on the trail‐making and 15‐object recognition tests.ConclusionOur findings suggest that the APOE‐ε4 genotype affects brain connectivity in regions previously found to be abnormal in AD as a sign of very early disease‐related pathology. These differences were too subtle in healthy elderly to use EC for single‐subject prediction of APOE genotype.

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“…In contrast, pathological studies have reported associations between clinical profile and neuritic plaques only,31 or combined amyloid and neurofibrillary tangle pathology 32. Another factor may be that amyloid is an “upstream” factor in a cascade of events leading to neuronal damage and clinical symptoms 33. In this hypothesis, the severity of amyloid deposition would not reflect disease stage, but the presence of amyloid would be expected to be associated with more rapid disease progression.…”

Section: Discussionmentioning

confidence: 97%

Clinical and imaging correlates of amyloid deposition in dementia with Lewy bodies

et al. 2018

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Background: Amyloid deposition is common in dementia with Lewy bodies, but its pathophysiological significance is unclear. Objective: The objective of this study was to investigate the relationship between amyloid deposition and clinical profile, gray matter volume, and brain perfusion in dementia with Lewy bodies. Methods: Dementia with Lewy bodies (n = 37), Alzheimer's disease (n = 20), and controls (n = 20) underwent a thorough clinical assessment, 3T MRI, and early‐ and late‐phase 18F‐Florbetapir PET‐CT to assess cortical perfusion and amyloid deposition, respectively. Amyloid scans were visually categorized as positive or negative. Image analysis was carried out using statistical parametric mapping (SPM) 8. Results: There were no significant differences between amyloid‐positive and amyloid‐negative dementia with Lewy bodies cases in age (P = .78), overall cognitive impairment (P = .83), level of functional impairment (P = .80), or any other clinical or cognitive scale. There were also no significant differences in hippocampal or gray matter volumes. However, amyloid‐positive dementia with Lewy bodies cases had lower medial temporal lobe perfusion (P = .03) than amyloid‐negative cases, although a combination of medial temporal lobe perfusion, hippocampal volume, and cognitive measures was unable to accurately predict amyloid status in dementia with Lewy bodies. Conclusions: Amyloid deposition was not associated with differences in clinical or neuropsychological profiles in dementia with Lewy bodies, but was associated with imaging evidence of medial temporal lobe dysfunction. The presence of amyloid in dementia with Lewy bodies cannot be identified on the basis of clinical and other imaging features and will require direct assessment via PET imaging or CSF. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

Cited by 3,430 publications

References 121 publications

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

Clinical and imaging correlates of amyloid deposition in dementia with Lewy bodies

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