Dataset Information

Brainstem Volumetric Integrity in Preclinical and Prodromal Alzheimer's Disease.

ABSTRACT:

Background

Neuropathological studies have suggested the tau pathology observed in Alzheimer's disease (AD) originates in brainstem nuclei, but no studies to date have quantified brainstem volumes in clinical populations with biomarker-confirmed mild cognitive impairment (MCI) or dementia due to AD or determined the value of brainstem volumetrics in predicting dementia.

Objective

The present study examined whether MRI-based brainstem volumes differ among cognitively normal older adults and those with MCI or dementia due to AD and whether preclinical brainstem volumes predict future progression to dementia.

Methods

Alzheimer's Disease Neuroimaging Initiative participants (N?=?1,629) underwent baseline MRI scanning with variable clinical follow-up (6-120 months). Region of interest and voxel-based morphometric methods assessed brainstem volume differences among cognitively normal (n?=?814), MCI (n?=?542), and AD (n?=?273) participants, as well as subsets of cerebrospinal fluid biomarker-confirmed MCI (n?=?203) and AD (n?=?160) participants.

Results

MCI and AD cases showed smaller midbrain volumes relative to cognitively normal participants when normalizing to whole brainstem volume, and showed smaller midbrain, locus coeruleus, pons, and whole brainstem volumes when normalizing to total intracranial volume. Cognitively normal individuals who later progressed to AD dementia diagnosis exhibited smaller baseline midbrain volumes than individuals who did not develop dementia, and voxel-wise analyses revealed specific volumetric reduction of the locus coeruleus.

Conclusion

Findings are consistent with neuropathological observations of early AD-related pathology in brainstem nuclei and further suggest the clinical relevance of brainstem substructural volumes in preclinical and prodromal AD.

SUBMITTER: Dutt S

PROVIDER: S-EPMC7868064 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Brainstem Volumetric Integrity in Preclinical and Prodromal Alzheimer's Disease.

Dutt Shubir S Li Yanrong Y Mather Mara M Nation Daniel A DA

Journal of Alzheimer's disease : JAD 20200101 4

<h4>Background</h4>Neuropathological studies have suggested the tau pathology observed in Alzheimer's disease (AD) originates in brainstem nuclei, but no studies to date have quantified brainstem volumes in clinical populations with biomarker-confirmed mild cognitive impairment (MCI) or dementia due to AD or determined the value of brainstem volumetrics in predicting dementia.<h4>Objective</h4>The present study examined whether MRI-based brainstem volumes differ among cognitively normal older ad ...[more]

PMID: 32925030

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Project description:Biomarkers useful for the predementia stages of Alzheimer's disease are needed. Electroencephalography and magnetoencephalography (MEG) are expected to provide potential biomarker candidates for evaluating the predementia stages of Alzheimer's disease. However, the physiological relevance of EEG/MEG signal changes and their role in pathophysiological processes such as amyloid-? deposition and neurodegeneration need to be elucidated. We evaluated 28 individuals with mild cognitive impairment and 38 cognitively normal individuals, all of whom were further classified into amyloid-?-positive mild cognitive impairment (n = 17, mean age 74.7 ± 5.4 years, nine males), amyloid-?-negative mild cognitive impairment (n = 11, mean age 73.8 ± 8.8 years, eight males), amyloid-?-positive cognitively normal (n = 13, mean age 71.8 ± 4.4 years, seven males), and amyloid-?-negative cognitively normal (n = 25, mean age 72.5 ± 3.4 years, 11 males) individuals using Pittsburgh compound B-PET. We measured resting state MEG for 5 min with the eyes closed, and investigated regional spectral patterns of MEG signals using atlas-based region of interest analysis. Then, the relevance of the regional spectral patterns and their associations with pathophysiological backgrounds were analysed by integrating information from Pittsburgh compound B-PET, fluorodeoxyglucose-PET, structural MRI, and cognitive tests. The results demonstrated that regional spectral patterns of resting state activity could be separated into several types of MEG signatures as follows: (i) the effects of amyloid-? deposition were expressed as the alpha band power augmentation in medial frontal areas; (ii) the delta band power increase in the same region was associated with disease progression within the Alzheimer's disease continuum and was correlated with entorhinal atrophy and an Alzheimer's disease-like regional decrease in glucose metabolism; and (iii) the global theta power augmentation, which was previously considered to be an Alzheimer's disease-related EEG/MEG signature, was associated with general cognitive decline and hippocampal atrophy, but was not specific to Alzheimer's disease because these changes could be observed in the absence of amyloid-? deposition. The results suggest that these MEG signatures may be useful as unique biomarkers for the predementia stages of Alzheimer's disease.

Project description:BackgroundProdromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease.MethodsWe conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function.ResultsThe trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group.ConclusionsVerubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).

Dataset Information

Brainstem Volumetric Integrity in Preclinical and Prodromal Alzheimer's Disease.

Background

Objective

Methods

Results

Conclusion

Publications

Brainstem Volumetric Integrity in Preclinical and Prodromal Alzheimer's Disease.

Similar Datasets

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