Development and assessment of a composite score for memory in the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
ABSTRACT We sought to develop and evaluate a composite memory score from the neuropsychological battery used in the Alzheimer's Disease (AD) Neuroimaging Initiative (ADNI). We used modern psychometric approaches to analyze longitudinal Rey Auditory Verbal Learning Test (RAVLT, 2 versions), AD Assessment Schedule - Cognition (ADAS-Cog, 3 versions), Mini-Mental State Examination (MMSE), and Logical Memory data to develop ADNI-Mem, a composite memory score. We compared RAVLT and ADAS-Cog versions, and compared ADNI-Mem to RAVLT recall sum scores, four ADAS-Cog-derived scores, the MMSE, and the Clinical Dementia Rating Sum of Boxes. We evaluated rates of decline in normal cognition, mild cognitive impairment (MCI), and AD, ability to predict conversion from MCI to AD, strength of association with selected imaging parameters, and ability to differentiate rates of decline between participants with and without AD cerebrospinal fluid (CSF) signatures. The second version of the RAVLT was harder than the first. The ADAS-Cog versions were of similar difficulty. ADNI-Mem was slightly better at detecting change than total RAVLT recall scores. It was as good as or better than all of the other scores at predicting conversion from MCI to AD. It was associated with all our selected imaging parameters for people with MCI and AD. Participants with MCI with an AD CSF signature had somewhat more rapid decline than did those without. This paper illustrates appropriate methods for addressing the different versions of word lists, and demonstrates the additional power to be gleaned with a psychometrically sound composite memory score.
SourceAvailable from: Jon Toledo[Show abstract] [Hide abstract]
ABSTRACT: Alzheimer's disease (AD) is characterized by the deposition of tau and amyloid in the brain. Although the core cerebrospinal fluid (CSF) AD biomarkers amyloid β peptide 1-42 (Aβ1-42), total tau (t-tau) and phosphorylated tau 181 (p-tau181) show good diagnostic sensitivity and specificity, additional biomarkers that can aid in preclinical diagnosis or better track disease progression are needed. Activation of the complement system, a pivotal part of inflammation, occurs at very early stages in the AD brain. Therefore, CSF levels of complement proteins that could be linked to cognitive and structural changes in AD may have diagnostic and prognostic value. Using xMAP® technology based assays we measured complement 3 (C3) and factor H (FH) in the CSF of 110 controls (CN), 187 mild cognitive impairment (MCI) and 92 AD subjects of the AD Neuroimaging Initiative (ADNI) at baseline. All ADNI participants underwent clinical follow-up at 12 month intervals and MCI subjects had additional visits at 6 and 18 months. The association between CSF biomarkers and different outcome measures were analyzed using Cox proportional hazard models (conversion from MCI to AD), logistic regression models (classification of clinical groups) and mixed-effects models adjusted for age, gender, education, t-tau/Aβ1-42 and APOE ϵ4 presence (baseline and longitudinal association between biomarkers and cognitive scores). Although no association was found between the complement proteins and clinical diagnosis or cognitive measures, lower levels of C3 (β = -0.12, p = 0.041) and FH (β = -0.075, p = 0.041) were associated with faster cognitive decline in MCI subjects as measured by the AD Assessment Scale-cognitive subscale (ADAS-Cog) test. Furthermore, lower FH levels were associated with larger lateral ventricular volume (p = 0.024), which is indicative of brain atrophy. Our study confirms a lack of suitability of CSF C3 and FH as diagnostic biomarkers of AD, but points to their modest potential as prognostic biomarkers and therapeutic targets in cognitively impaired patients.Alzheimer's Research and Therapy 06/2014; 6(3):36. DOI:10.1186/alzrt266 · 3.50 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: A subset of older adults present post mortem with Alzheimer disease (AD) pathologic features but without any significant clinical manifestation of dementia. Vascular endothelial growth factor (VEGF) has been implicated in staving off AD-related neurodegeneration. To evaluate whether VEGF levels are associated with brain aging outcomes (hippocampal volume and cognition) and to further evaluate whether VEGF modifies relations between AD biomarkers and brain aging outcomes. Biomarker analysis using neuroimaging and neuropsychological outcomes from the Alzheimer's Disease Neuroimaging Initiative. This prospective longitudinal study across North America included individuals with normal cognition (n = 90), mild cognitive impairment (n = 130), and AD (n = 59) and began in October 2004, with follow-up ongoing. Cerebrospinal fluid VEGF was cross-sectionally related to brain aging outcomes (hippocampal volume, episodic memory, and executive function) using a general linear model and longitudinally using mixed-effects regression. Alzheimer disease biomarker (cerebrospinal fluid β-amyloid 42 and total tau)-by-VEGF interactions evaluated the effect of VEGF on brain aging outcomes in the presence of enhanced AD biomarkers. Vascular endothelial growth factor was associated with baseline hippocampal volume (t277 = 2.62; P = .009), longitudinal hippocampal atrophy (t858 = 2.48; P = .01), and longitudinal decline in memory (t1629 = 4.09; P < .001) and executive function (t1616 = 3.00; P = .003). Vascular endothelial growth factor interacted with tau in predicting longitudinal hippocampal atrophy (t845 = 4.17; P < .001), memory decline (t1610 = 2.49; P = .01), and executive function decline (t1597 = 3.71; P < .001). Vascular endothelial growth factor interacted with β-amyloid 42 in predicting longitudinal memory decline (t1618 = -2.53; P = .01). Elevated cerebrospinal fluid VEGF was associated with more optimal brain aging in vivo. The neuroprotective effect appeared strongest in the presence of enhanced AD biomarkers, suggesting that VEGF may be particularly beneficial in individuals showing early hallmarks of the AD cascade. Future work should evaluate the interaction between VEGF expression in vitro and pathologic burden to address potential mechanisms.JAMA Neurology 03/2015; 72(5). DOI:10.1001/jamaneurol.2014.4761 · 7.01 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Background: The purpose of the current study was to test the hypothesis that anxiety in amnestic mild cognitive impairment (aMCI) increases rates of conversion to Alzheimer’s disease (AD), and to identify potential neural mechanisms underlying such an association. Methods: 376 participants with aMCI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were studied over a median period of 36 months. A Cox proportional-hazards model was used to assess the association between anxiety severity ratings on the Neuropsychiatric Inventory Questionnaire and AD risk. Other variables included in the model were depression, memory loss, and MRI-derived AD-related regions-of-interest (ROI), including hippocampal (HC), amygdalar (AMYG), entorhinal cortical (EC) volumes and EC thickness, In addition, a linear regression model was used to determine the effect of anxiety in aMCI on rates of atrophy within ROIs. Results: Anxiety severity increased rate of aMCI conversion to AD, after controlling for depression and cognitive decline. The association between anxiety and AD remained significant even with inclusion of ROI baseline values or atrophy rates as explanatory variables. Further, anxiety status predicted greater rates of decrease in EC volume and was marginally associated specifically with EC-thickness. Conclusions: Anxiety symptoms in aMCI predict conversion to AD, over and beyond the effects of depression, memory loss, or atrophy within AD neuroimaging biomarkers. These findings, together with the greater EC atrophy rate predicted by anxiety, are compatible with the hypothesis that anxiety is not a prodromal non-cognitive feature of AD, but may accelerate decline towards AD through direct or indirect effects on EC.The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 10/2014; 23(5). DOI:10.1016/j.jagp.2014.10.005 · 3.52 Impact Factor