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Amyloid pathology in the progression to mild cognitive impairment.

ABSTRACT: The objective of this study was to determine the cognitive and functional decline and development of brain injury in individuals progressing from preclinical (?-amyloid positive cognitively normal) to prodromal Alzheimer's disease (AD) (?-amyloid positive mild cognitive impairment [MCI]), and compare this with individuals who progress to MCI in the absence of significant amyloid pathology. Seventy-five cognitively healthy participants who progressed to MCI were followed for 4 years on average and up to 10 years. We tested effects of ?-amyloid (A?) on measures of cognition, functional status, depressive symptoms, and brain structure and metabolism. Preclinical AD subjects showed greater cognitive decline in multiple domains and increased cerebrospinal fluid phosphorylated tau levels at baseline while A?-negative progressors showed increased rates of white matter hyperintensity accumulation and had a greater frequency of depressive symptoms at baseline. A? status did not influence patterns of brain atrophy, but preclinical AD subjects showed greater decline of brain metabolism than A?-negative progressors. Several unique features separate the transition from preclinical to prodromal AD from other causes of cognitive decline. These features may facilitate early diagnosis and treatment of AD, especially in clinical trials aimed at halting the progression from preclinical to prodromal AD.

SUBMITTER: Insel PS

PROVIDER: S-EPMC5820200 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Amyloid pathology in the progression to mild cognitive impairment.

Insel Philip S PS Hansson Oskar O Mackin R Scott RS Weiner Michael M Mattsson Niklas N

Neurobiology of aging 20171227

The objective of this study was to determine the cognitive and functional decline and development of brain injury in individuals progressing from preclinical (β-amyloid positive cognitively normal) to prodromal Alzheimer's disease (AD) (β-amyloid positive mild cognitive impairment [MCI]), and compare this with individuals who progress to MCI in the absence of significant amyloid pathology. Seventy-five cognitively healthy participants who progressed to MCI were followed for 4 years on average an ...[more]

PMID: 29353101

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Project description:BackgroundAmyloid pathology in subjects with mild cognitive impairment (MCI) is an important risk factor for progression to dementia due to Alzheimer's disease. Predicting the onset of dementia is challenging even in the presence of amyloid, as time to progression varies considerably among patients and depends on the onset of neurodegeneration. Survival analysis can account for variability in time to event, but has not often been applied to MRI measurements beyond singular predefined brain regions such as the hippocampus. Here we used a voxel-wise survival analysis to identify in an unbiased fashion brain regions where decreased gray matter volume is associated with time to dementia, and assessed the effects of amyloid on these associations.MethodsWe included 276 subjects with MCI (mean age 67?±?8, 41% female, mean Mini-Mental State Examination 26.6?±?2.4), baseline 3D T1-weighted structural MRI, baseline cerebrospinal fluid (CSF) biomarkers, and prospective clinical follow-up. We fitted for each voxel a proportional Cox hazards regression model to study whether decreased gray matter volume predicted progression to dementia in the total sample, and stratified for baseline amyloid status.ResultsDementia at follow-up occurred in 122 (44%) subjects over an average follow-up period of 2.5?±?1.5 years. Baseline amyloid positivity was associated with progression to dementia (hazard ratio 2.4, p?<?0.001). Within amyloid-positive subjects, decreased gray matter volume in the hippocampal, temporal, parietal, and frontal regions was associated with more rapid progression to dementia (median (interquartile range) hazard ratio across significant voxels 1.35 (1.32-1.40)). Repeating the analysis in amyloid-negative subjects revealed similar patterns (median (interquartile range) hazard ratio 1.76 (1.66-1.91)).ConclusionsIn subjects with MCI, both abnormal amyloid CSF and decreased gray matter volume were associated with future progression to dementia. The spatial pattern of decreased gray matter volume associated with progression to dementia was consistent for amyloid-positive and amyloid-negative subjects.

Project description:BackgroundAccording to the amyloid, tau, neurodegeneration research framework classification, amyloid and tau positive (A+T+) mild cognitive impairment (MCI) individuals are defined as prodromal Alzheimer disease. This study was designed to compare the clinical and biomarker features between A+T+MCI individuals who progressed to progressive MCI (pMCI) and those who remained stable MCI (sMCI), and to identify relevant baseline clinical biomarker and features that could be used to predict progression to dementia within 2 years.MethodsWe stratified 197 A+T+MCI individuals into pMCI (n = 64) and sMCI (n = 133) over 2 years. Demographics and cognitive assessment scores, cerebrospinal fluid (CSF), and neuroimaging biomarkers (18F-florbetapir positron emission tomography mean standardized uptake value ratios [SUVR] and structural magnetic resonance imaging [MRI]) were compared between pMCI and sMCI at baseline, 12- and 24-month follow-up. Logistic regression models then were used to evaluate clinical baseline and biomarker features that predicted dementia progression in A+T+MCI.ResultspMCI individuals had higher mean 18F-florbetapir SUVR, CSF total-tau (t-tau), and p-tau181P than those in sMCI individuals. pMCI individuals performed poorer in cognitive assessments, both global and domain specific (memory, executive, language, attention, and visuospatial skills) than sMCI. At baseline, there were significant differences in regions of interest of structural MRI between the two groups, including bilateral amygdala, hippocampus and entorhinal, bilateral inferior lateral ventricle, left superior and middle temporal, left posterior and caudal anterior cingulate (P < 0.05). Baseline CSF t-tau levels and cognitive scores of Montreal cognitive assessment, functional assessment questionnaire, and everyday cognition by the patient's study partner language domain could predict progression to dementia in A+T+MCI within 2 years.ConclusionsIn future clinical trials, specific CSF and cognitive measures that predict dementia progression in A+T+MCI might be useful risk factors for assessing the risk of dementia progression.

Project description:The amyloid framework forms the central medical theory related to Alzheimer disease (AD), and the in vivo demonstration of amyloid positivity is essential for diagnosing AD. On the basis of a longitudinal cohort design, the study investigated clinical progressive patterns by obtaining cognitive and structural measurements from a group of patients with amnestic mild cognitive impairment (MCI); the measurements were classified by the positivity (Aβ+) or absence (Aβ-) of the amyloid biomarker. We enrolled 185 patients (64 controls, 121 patients with MCI). The patients with MCI were classified into two groups on the basis of their [18F]flubetaben or [18F]florbetapir amyloid positron-emission tomography scan (Aβ+ vs. Aβ-, 67 vs. 54 patients) results. Data from annual cognitive measurements and three-dimensional T1 magnetic resonance imaging scans were used for between-group comparisons. To obtain longitudinal cognitive test scores, generalized estimating equations were applied. A linear mixed effects model was used to compare the time effect of cortical thickness degeneration. The cognitive decline trajectory of the Aβ+ group was obvious, whereas the Aβ- and control groups did not exhibit a noticeable decline over time. The group effects of cortical thickness indicated decreased entorhinal cortex in the Aβ+ group and supramarginal gyrus in the Aβ- group. The topology of neurodegeneration in the Aβ- group was emphasized in posterior cortical regions. A comparison of the changes in the Aβ+ and Aβ- groups over time revealed a higher rate of cortical thickness decline in the Aβ+ group than in the Aβ- group in the default mode network. The Aβ+ and Aβ- groups experienced different APOE ε4 effects. For cortical-cognitive correlations, the regions associated with cognitive decline in the Aβ+ group were mainly localized in the perisylvian and anterior cingulate regions. By contrast, the degenerative topography of Aβ- MCI was scattered. The memory learning curves, cognitive decline patterns, and cortical degeneration topographies of the two MCI groups were revealed to be different, suggesting a difference in pathophysiology. Longitudinal analysis may help to differentiate between these two MCI groups if biomarker access is unavailable in clinical settings.

Project description:BACKGROUND:Determination of β-amyloid (Aβ) positivity and likelihood of underlying Alzheimer's disease (AD) relies on dichotomous biomarker cut-off values. Individuals with mild cognitive impairment (MCI) and Aβ within the normal range may still have a substantial risk of developing dementia, primarily of Alzheimer type. Their prognosis, as well as predictors of clinical progression, are not fully understood. The aim of this study was to explore the associations of cerebrospinal fluid (CSF) biomarkers (Aβ42, total tau, phosphorylated tau) and other characteristics, including modifiable vascular factors, with the risk of progression to dementia among patients with MCI and normal CSF Aβ42. METHODS:Three hundred eighteen memory clinic patients with CSF and clinical data, and at least 1-year follow-up, were included. Patients had normal CSF Aβ42 levels based on clinical cut-offs. Cox proportional hazard models with age as time scale and adjusted for sex, education, and cognition (Mini-Mental State Examination) were used to investigate predictors of progression to dementia and Alzheimer-type dementia. Potential predictors included CSF biomarkers, cognitive performance (verbal learning and memory), apolipoprotein E (APOE) ε4 genotype, medial temporal lobe atrophy, family history of dementia, depressive symptoms, and vascular factors, including the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score. Predictive performance of patient characteristics was further explored with Harrell C statistic. RESULTS:Lower normal Aβ42 and higher total tau and phosphorylated tau were associated with higher dementia risk, and the association was not driven by Aβ42 values close to cut-off. Additional predictors included poorer cognition, APOE ε4 genotype, higher systolic blood pressure, and lower body mass index, but not the CAIDE dementia risk score. Aβ42 individually and in combination with other CSF biomarkers improved the risk prediction compared to age and cognition alone. Medial temporal lobe atrophy or vascular factors did not increase the predictive performance. CONCLUSIONS:Possibility of underlying AD pathology and increased dementia risk should not be ruled out among MCI patients with CSF Aβ42 within the normal range. While cut-offs may be useful in clinical practice to identify high-risk individuals, personalized risk prediction tools incorporating continuous biomarkers may be preferable among individuals with intermediate risk. The role of modifiable vascular factors could be explored in this context.

Dataset Information

Amyloid pathology in the progression to mild cognitive impairment.

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Amyloid pathology in the progression to mild cognitive impairment.

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