This is where I blame the mentors and senior researchers for totally fucking up what needs to be researched. We don't need research on predicting bad things happening. We need research on stopping those bad things from happening. Are you that much of blithering idiots out there? If your leaders aren't leading, forge your own path.
Predicting Cognitive Decline in Older Adults Using Baseline Metrics of AD Pathologies, Cerebrovascular Disease, and Neurodegeneration
Abstract
Background and Objectives Dementia is a growing socioeconomic challenge that requires early intervention. (With what? THAT is the research you should be doing!)Identifying biomarkers that reliably predict clinical progression early in the disease process would better aid selection of individuals for future trial participation. Here, we compared the ability of baseline, single time-point biomarkers (CSF amyloid 1–42, CSF ptau-181, white matter hyperintensities (WMH), cerebral microbleeds, whole-brain volume, and hippocampal volume) to predict decline in cognitively normal individuals who later converted to mild cognitive impairment (MCI) (CNtoMCI) and those with MCI who later converted to an Alzheimer disease (AD) diagnosis (MCItoAD).
Methods Standardized baseline biomarker data from AD Neuroimaging Initiative 2 (ADNI2)/GO and longitudinal diagnostic data (including ADNI3) were used. Cox regression models assessed biomarkers in relation to time to change in clinical diagnosis using all follow-up time points available. Models were fit for biomarkers univariately and together in a multivariable model. Hazard ratios (HRs) were compared to evaluate biomarkers. Analyses were performed separately in CNtoMCI and MCItoAD groups.
Results For CNtoMCI (n = 189), there was strong evidence that higher WMH volume (individual model: HR 1.79, p = 0.002; fully adjusted model: HR 1.98, p = 0.003) and lower hippocampal volume (individual: HR 0.54, p = 0.001; fully adjusted: HR 0.40, p < 0.001) were associated with conversion to MCI individually and independently. For MCItoAD (n = 345), lower hippocampal (individual model: HR 0.45, p < 0.001; fully adjusted model: HR 0.55, p < 0.001) and whole-brain volume (individual: HR 0.31, p < 0.001; fully adjusted: HR 0.48, p = 0.02), increased CSF ptau (individual: HR 1.88, p < 0.001; fully adjusted: HR 1.61, p < 0.001), and lower CSF amyloid (individual: HR 0.37, p < 0.001; fully adjusted: HR 0.62, p = 0.008) were most strongly associated with conversion to AD individually and independently.
Discussion Lower hippocampal volume was a consistent predictor of clinical conversion to MCI and AD. CSF and brain volume biomarkers were predictive of conversion to AD from MCI, whereas WMH were predictive of conversion to MCI from cognitively normal. The predictive ability of WMH in the CNtoMCI group may be interpreted as some being on a different pathologic pathway, such as vascular cognitive impairment.
- Figure 1 Hazard Ratios in the CNtoMCI Group
HR scores (along with upper and lower CI limits) from the Cox regression models separately and in the fully adjusted model (containing all biomarkers), with age adjustment. Individual models, WMH, hippocampal volume, and whole-brain volume, and the fully adjusted model were TIV adjusted. The proportional hazard (PH) assumption was met in all instances (p > 0.05, all tests). The individual bars visually represent these HRs along with their uncertainty around the estimate (upper and lower limits). Bars below 1 highlight that decreased levels of the biomarker are associated with progression, whereas bars above 1 highlight that increased levels of the biomarker are associated with progression. Bars crossing 1 are not significantly associated with clinical progression. CN = cognitively normal; HR = hazard ratio; TIV = total intracranial volume; WMH = white matter hyperintensities.
- Figure 2 Kaplan-Meier Survival Estimates in the CNtoMCI Group
(A and B) Kaplan-Meier curves of the two separately and independently significant predictors in both individual and fully adjusted Cox regression models (WMH and hippocampal volume) for the CNtoMCI group. Continuous variables have been dichotomized at a median point, with shaded regions representing 95% CI. CN = cognitively normal; MCI = mild cognitive impairment; WMH = white matter hyperintensities.
- Figure 3 Hazard Ratios in the MCItoAD Group
Hazard ratios and their upper and lower limits from both individual and fully adjusted models for the MCItoAD group with age adjustment. Individual models, WMH, hippocampal volume, and whole-brain volume, and the fully adjusted model were TIV adjusted. The proportional hazards assumption was met in all individual models (p > 0.05, all tests) excluding hippocampal volume, so a time varying coefficient (TVC) was included to account for this. In the fully adjusted model, this assumption was not met for whole-brain volume or for hippocampal volume (p < 0.05, both tests) and was accounted for with a TVC correction. A TVC correction was also applied to age. The individual bars visually represent these HRs along with their uncertainty around the estimate (upper and lower limits). Bars below 1 highlight that decreased levels of the biomarker are associated with progression, whereas bars above 1 highlight that increased levels of the biomarker are associated with progression. Bars crossing 1 are not significantly associated with clinical progression. AD = Alzheimer disease; HR = hazard ratio; MCI = mild cognitive impairment; WMH = white matter hyperintensities.
- Figure 4 Kaplan-Meier Survival Estimates in the MCItoAD Group
(A–D) Kaplan-Meier curves of the three separately and independently significant predictors in both individual and fully adjusted Cox regression models (CSF amyloid, CSF ptau, hippocampal volume, and whole-brain volume), displaying their individual predictive power over time by median split or gaussian mixture model cutpoint (raw CSF amyloid cutpoint of 256 pg/mL). Shaded regions represent 95% CI. AD = Alzheimer disease; MCI = mild cognitive impairment.
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