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Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer's Coordinating Center Uniform Data Set.

ABSTRACT: BACKGROUND:Longitudinal investigations are needed to improve understanding of the contributions of cerebral small vessel disease to the clinical manifestation of Alzheimer's disease, particularly in the early disease stages. This study leveraged the National Alzheimer's Coordinating Center Uniform Data Set to longitudinally examine the association between white matter hyperintensities and neuropsychological, neuropsychiatric, and functional decline among participants with normal cognition. METHODS:The sample included 465 participants from the National Alzheimer's Coordinating Center Uniform Data Set who had quantitated volume of white matter hyperintensities from fluid-attenuated inversion recovery MRI, had normal cognition at the time of their MRI, and were administered the National Alzheimer's Coordinating Center Uniform Data Set neuropsychological test battery within 1?year of study evaluation and had at least two post-MRI time points of clinical data. Neuropsychiatric status was assessed by the Geriatric Depression Scale-15 and Neuropsychiatric Inventory-Questionnaire. Clinical Dementia Rating Sum of Boxes defined functional status. For participants subsequently diagnosed with mild cognitive impairment (MCI) or dementia, their impairment must have been attributed to Alzheimer's disease (AD) to evaluate the relationships between WMH and the clinical presentation of AD. RESULTS:Of the 465 participants, 56 converted to MCI or AD dementia (average follow-up?=?5?years). Among the 465 participants, generalized estimating equations controlling for age, sex, race, education, APOE ?4, and total brain and hippocampal volume showed that higher baseline log-white matter hyperintensities predicted accelerated decline on the following neuropsychological tests in rank order of effect size: Trails B (p?

SUBMITTER: Puzo C

PROVIDER: S-EPMC6661103 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer's Coordinating Center Uniform Data Set.

Puzo Christian C Labriola Caroline C Sugarman Michael A MA Tripodis Yorghos Y Martin Brett B Palmisano Joseph N JN Steinberg Eric G EG Stein Thor D TD Kowall Neil W NW McKee Ann C AC Mez Jesse J Killiany Ronald J RJ Stern Robert A RA Alosco Michael L ML

Alzheimer's research & therapy 20190727 1

<h4>Background</h4>Longitudinal investigations are needed to improve understanding of the contributions of cerebral small vessel disease to the clinical manifestation of Alzheimer's disease, particularly in the early disease stages. This study leveraged the National Alzheimer's Coordinating Center Uniform Data Set to longitudinally examine the association between white matter hyperintensities and neuropsychological, neuropsychiatric, and functional decline among participants with normal cognitio ...[more]

PMID: 31351489

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Project description:BackgroundNeuropsychiatric symptoms (NPSs) are common in Alzheimer's disease (AD). NPSs contribute to patients' distress, caregiver burden, and institutionalization. White matter hyperintensities (WMHs) appear on magnetic resonance imaging, usually indicative of cerebrovascular disease. WMHs have been associated with certain NPSs. We aimed to assess the relationship between WMH and NPS severity in mild cognitive impairment (MCI) due to AD (MCI-AD) and in AD and to assess the ability of WMHs to predict NPS progression. Data were obtained from the National Alzheimer's Coordinating Center.MethodsA total of 252 participants (114 with MCI-AD and 138 with AD) were used in this study. Baseline WMHs were quantified using an automated segmentation technique. NPSs were measured using the Neuropsychiatric Inventory. Mixed-effect models and correlations were used to determine the relationship between WMHs and NPSs.ResultsLongitudinal mixed-effect models revealed a significant relationship between increase in Neuropsychiatric Inventory total scores and baseline WMHs (p = .014). There was a significant relationship between baseline WMHs and an increase in delusions (p = .023), hallucinations (p = .040), agitation (p = .093), depression (p = .017), and irritability (p = .002). Correlation plot analysis showed that baseline whole-brain WMHs predicted change in future Neuropsychiatric Inventory total scores (r = .169, p = .008) and predicted change in future agitation severity scores (r = .165, p = .009). WMHs in the temporal lobes (r = .169, p = .008) and frontal lobes (r = .153, p = .016) contributed most to this change.ConclusionsDepression, irritability, and agitation are common NPSs and very distressful to patients and caregivers. Our findings of increased NPS severity over time in MCI-AD and AD with increased WMHs have important implications for treatment, arguing for aggressive treatment of vascular risk factors in patients with MCI-AD or AD.

Project description:ImportanceAlthough white matter hyperintensities (WMHs) are associated with the risk for Alzheimer disease, it is unknown whether they represent an independent source of impairment or interact with known markers of disease.ObjectiveTo examine the degree to which WMHs predict aggressive cognitive decline among individuals with mild cognitive impairment, either independently or by modifying the effects of entorhinal cortex volume (ECV), a marker of Alzheimer disease-related neurodegeneration.Design, setting, and participantsThe Alzheimer's Disease Neuroimaging Initiative is a longitudinal study with 6-month follow-up visits. Three hundred thirty-two participants (mean [SD] age, 74.6 [7.4] years; 118 women) of a total of 374 participants diagnosed as having mild cognitive impairment were included. Participants were excluded if they did not have longitudinal data, apolipoprotein E genotype data, or had evidence of supratentorial infarct.Main outcomes and measuresA decline in Mini-Mental State Examination score of 3 points over 6 months or 6 points over 1 year between consecutive visits was defined as aggressive decline. White matter hyperintensity volume and ECV were entered as predictors in Cox proportional hazards models and Wilcoxon-Breslow tests to examine their impact on this outcome, adjusting for sex, age, education, and apolipoprotein E status.ResultsGreater WMH volume at baseline, apolipoprotein E ε4 status, and smaller ECV at baseline were associated with an increased risk for aggressive decline (hazard ratio [HR], 1.23; 95% CI, 1.05-1.43; P = .01 for WMH volume; HR, 1.49; 95% CI, 1.09-2.05; P = .04 for apolipoprotein E ε4 status; HR, 0.66; 95% CI, 0.55-0.79; P < .001 for ECV). White matter hyperintensity volume modified the effect of ECV on aggressive decline risk: individuals with high ECV and low WMH were at particularly low likelihood of decline (χ2 = 15, P = .001). Participants with Mini-Mental State Examination scores that declined by 3 or more points over 6 months or 6 or more points over 12 months were more likely to have converted to Alzheimer disease by the end of the follow-up period (χ2 = 82, P < .001).Conclusions and relevanceWhite matter hyperintensity burden and ECV predict rapid cognitive decline among individuals with mild cognitive impairment both additively and multiplicatively.

Dataset Information

Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer's Coordinating Center Uniform Data Set.

Publications

Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer's Coordinating Center Uniform Data Set.

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