Biomarkers relevant to the pre-dementia stages of Alzheimer’s disease are needed. Using MEG, PET, and MRI, Nakamura et al. disentangle resting state regional spectral patterns in cognitively normal subjects and individuals with mild cognitive impairment into MEG signatures related to Aβ deposition, disease progression, or changes non-specific to Alzheimer’s disease.

Alzheimer’s disease (AD) is the most common and devastating dementia. Simple and practical biomarkers for AD are urgently required for accurate diagnosis and to facilitate the development of disease-modifying interventions. The subjects for the study were selected on the basis of PiB amyloid imaging by PET. Forty PiB-positive (PiB+) individuals, including cognitively healthy controls (HC), and mild cognitive impairment and AD individuals, and 22 PiB-negative (PiB−) HC participated. Employing our novel highly sensitive immunoprecipitation-mass spectrometry, we measured plasma amyloid β-proteins (Aβs; Aβ1-40 and Aβ1-42) and Aβ-approximate peptides (AβAPs), which were cleaved from amyloid precursor protein (APP). Among the AβAPs, APP669-711 appeared to be a good reference for deciphering pathological change of Aβ1-42. We evaluated the performance of the ratio of APP669-711 to Aβ1-42 (APP669-711/Aβ1-42) as a biomarker. APP669-711/Aβ1-42 significantly increased in the PiB+ groups. The sensitivity and specificity to discriminate PiB+ individuals from PiB− individuals were 0.925 and 0.955, respectively. Our plasma biomarker precisely surrogates cerebral amyloid deposition.

Amyloid-β (Aβ) deposition is known to starts decades before the onset of clinical symptoms of Alzheimer’s disease (AD), however, the detailed pathophysiological processes underlying this preclinical period are not well understood. This study aimed to investigate functional network alterations in cognitively intact elderly individuals at risk for AD, and assessed the association between these network alterations and changes in Aβ deposition, glucose metabolism, and brain structure. Forty-five cognitively normal elderly subjects, who were classified into Aβ-positive (CN+) and Aβ-negative (CN−) groups using 11C-Pittsburgh compound B PET, underwent resting state magnetoencephalography measurements, 18F-fluorodeoxyglucose PET (FDG-PET) and structural MRI. Results demonstrated that in the CN+ group, functional connectivity (FC) within the precuneus was significantly decreased, whereas it was significantly enhanced between the precuneus and the bilateral inferior parietal lobules in the low-frequency bands (theta and delta). These changes were suggested to be associated with local cerebral Aβ deposition. Most of Aβ+ individuals in this study did not show any metabolic or anatomical changes, and there were no significant correlations between FC values and FDG-PET or MRI volumetry data. These results demonstrate that functional network alterations, which occur in association with Aβ deposition, are detectable using magnetoencephalography before metabolic and anatomical changes are seen.

BackgroundAlzheimer’s disease (AD) is a most common dementia in elderly people. Since AD symptoms resemble those of other neurodegenerative diseases, including idiopathic normal pressure hydrocephalus (iNPH), it is difficult to distinguish AD from iNPH for a precise and early diagnosis. iNPH is caused by the accumulation of cerebrospinal fluid (CSF) and involves gait disturbance, urinary incontinence, and dementia. iNPH is treatable with shunt operation which removes accumulated CSF from the brain ventricles.MethodsWe performed metabolomic analysis in the CSF of patients with AD and iNPH with capillary electrophoresis-mass spectrometry. We assessed metabolites to discriminate between AD and iNPH with Welch’s t-test, receiver operating characteristic (ROC) curve analysis, and multiple logistic regression analysis.ResultsWe found significant increased levels of glycerate and N-acetylneuraminate and significant decreased levels of serine and 2-hydroxybutyrate in the CSF of patients with AD compared to the CSF of patients with iNPH. The ROC curve analysis with these four metabolites showed that the area under the ROC curve was 0.90, indicating good discrimination between AD and iNPH.ConclusionsThis study identified four metabolites that could possibly discriminate between AD and iNPH, which previous research has shown are closely related to the risk factors, pathogenesis, and symptoms of AD. Analyzing pathway-specific metabolites in the CSF of patients with AD may further elucidate the mechanism and pathogenesis of AD.Electronic supplementary materialThe online version of this article (10.1186/s40364-018-0119-x) contains supplementary material, which is available to authorized users.

Little is known about how ischemia affects hemodynamic responses to neural activation in the brain. We compare the effects of a motor activation task and a cerebral vasodilating agent, acetazolamide (ACZ), on regional cerebral blood flow (rCBF) in primary sensorimotor cortex (PSM) in six patients with major cerebral artery steno-occlusive lesions without paresis of the upper extremities. Quantitative rCBF was measured in all patients using H2(15)O autoradiographic method and positron emission tomography. The CBF was determined at rest, during a bimanual motor activation task, and 10 minutes after ACZ administration. With bimanual motor activation, rCBF increased significantly in both PSM compared with at rest (P < 0.01 on lesion side, and P < 0.02 on contralateral side). However, rCBF did not increase after ACZ injection in the PSM on the lesion side, whereas rCBF increased significantly in the contralateral PSM after ACZ injection compared with the level at rest. This result suggests that despite a decreased hemodynamic reserve, there is a nearly normal flow response to neural activation, indicating that the mechanism of vasodilation responsible for perfusion change is different for acetazolamide and neural activation. The relations among neural activation, hemodynamic status, and cerebral metabolism in the ischemic stroke patients are discussed.