Electromagnetic signatures of the preclinical and prodromal stages of Alzheimer's disease.

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-ß 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-ß-positive mild cognitive impairment (n = 17, mean age 74.7 ± 5.4 years, nine males), amyloid-ß-negative mild cognitive impairment (n = 11, mean age 73.8 ± 8.8 years, eight males), amyloid-ß-positive cognitively normal (n = 13, mean age 71.8 ± 4.4 years, seven males), and amyloid-ß-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-ß 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-ß deposition. The results suggest that these MEG signatures may be useful as unique biomarkers for the predementia stages of Alzheimer's disease.

Novel plasma biomarker surrogating cerebral amyloid deposition.

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 ß-proteins (Aßs; Aß1-40 and Aß1-42) and Aß-approximate peptides (AßAPs), which were cleaved from amyloid precursor protein (APP). Among the AßAPs, APP669-711 appeared to be a good reference for deciphering pathological change of Aß1-42. We evaluated the performance of the ratio of APP669-711 to Aß1-42 (APP669-711/Aß1-42) as a biomarker. APP669-711/Aß1-42 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.

Patterns of Distribution of 18F-THK5351 Positron Emission Tomography in Alzheimer's Disease Continuum.

BACKGROUND: Alzheimer's disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. OBJECTIVE: Using 18F-THK5351 as a tracer that binds to both tau and monoamine oxidase B (MAO-B), we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. METHODS: We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. RESULTS: On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. CONCLUSION: The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

Role of computerized tomographic cisternography in idiopathic normal pressure hydrocephalus.

BACKGROUND: We prospectively evaluate the role of computerized tomographic cisternography (CTC) in idiopathic normal pressure hydrocephalus (iNPH). METHODS: The cerebrospinal fluid kinetics of 70 patients who passed the entry criteria for the Study of iNPH on Neurological Improvement (SINPHONI) and underwent insertion of a shunt were studied. RESULTS: Stasis of the contrast medium at the lateral ventricles over 24 h (positive ventricular stasis) was observed in 60 patients and at the Sylvian fissure or parietal sulci over 48 h (positive surface stasis) in 59 patients. Sixty patients showed a good response to shunt insertion. The sensitivities of CTC findings at the lateral ventricles and brain surface for shunt effectiveness were 81.7 and 86.7%, respectively; however, the specificities were 20 and 0%. Among the 60 patients who showed a good response to the shunt, 49 had positive surface stasis. Positive ventricular stasis was observed in 52 of the 60 patients, and both findings were observed in 44 patients. Three patients who responded to the shunt had negative stasis in both sites. The 11 patients who had negative surface stasis had significantly lower (p < 0.05) preoperative iNPH grading scale-R scores than the 49 patients with positive surface stasis; these patients were considered to be in an early stage of iNPH. CONCLUSIONS: CTC did not provide additional diagnostic value for predicting the shunt response among patients selected using SINPHONI criteria. We suggest that factors other than disturbances in CSF circulation may be related to the pathogenesis of iNPH.

Can Medial Temporal Impairment Be an Imaging Red Flag for Neurodegeneration in Disproportionately Enlarged Subarachnoid Space Hydrocephalus?

BACKGROUND: The differentiation of idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative diseases such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is often challenging because of their non-specific symptoms. Therefore, various neuroradiological markers other than ventriculomegaly have been proposed. Despite the utility of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) for the appropriate selection of shunt surgery candidates, the specificity and neuropathology of this finding have not been sufficiently evaluated. OBJECTIVE: Investigation of the clinicopathological features and comparison of the neuroradiological findings between DESH with postmortem neuropathological diagnoses (pDESH) and clinically-diagnosed iNPH (ciNPH) patients are the main purposes of this study. METHOD: In addition to the retrospective evaluation of clinicopathological information, quantitative, semiquantitative, and qualitative magnetic resonance imaging (MRI) indices were compared between pathologically-investigated 10 patients with pDESH and 10 patients with ciNPHResults:Excluding one patient with multiple cerebral infarctions, the postmortem neuropathological diagnoses of the pathologically-investigated patients were mainly neurodegenerative diseases (five AD, one DLB with AD pathologies, one DLB, one argyrophilic grain disease, and one Huntington's disease). In addition to the common neuroradiological featuresConclusion:Hippocampal atrophy and deformation with temporal horn enlargement seem to be characteristic neuroradiological findings of long-standing severely demented patients with DESH and neurodegenerative diseases, mainly advanced-stage AD.

Comparative analysis of cerebrospinal fluid metabolites in Alzheimer's disease and idiopathic normal pressure hydrocephalus in a Japanese cohort.

BACKGROUND: Alzheimer'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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: This 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.

Early functional network alterations in asymptomatic elders at risk for Alzheimer's disease.

Amyloid-ß (Aß) 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 Aß deposition, glucose metabolism, and brain structure. Forty-five cognitively normal elderly subjects, who were classified into Aß-positive (CN+) and Aß-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 Aß deposition. Most of Aß+ 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 Aß deposition, are detectable using magnetoencephalography before metabolic and anatomical changes are seen.

Decreased Glucose Metabolism in Medial Prefrontal Areas is Associated with Nutritional Status in Patients with Prodromal and Early Alzheimer's Disease.

BACKGROUND: Weight loss is frequently observed in patients with Alzheimer's disease (AD); however, the underlying mechanisms are not well understood. OBJECTS: To clarify the associations between nutritional status and AD-related brain changes using Pittsburgh Compound-B (PiB)-PET, fluorodeoxyglucose (FDG)-PET, and structural MRI. METHODS: The subjects were 34 amyloid-ß (Aß)-positive individuals with mild cognitive impairment or early AD (prodromal/early AD), and 55 Aß-negative cognitively normal (CN) subjects who attended the Multimodal Neuroimaging for AD Diagnosis (MULNIAD) study. Nutritional status of the subjects was assessed by body mass index and waist to height ratio (waist circumference/height). The associations between nutritional status and brain changes were examined by multiple regression analysis using statistical parametric mapping. RESULTS: In the prodromal/early AD group, nutritional status was significantly positively correlated with regional cerebral glucose metabolism (rCGM) in the medial prefrontal cortices, while different topographical associations were seen in the CN group, suggesting these changes were AD-specific. Aß deposition and gray matter volume were not significantly associated with nutritional status. Sub-analysis in the prodromal/early AD group demonstrated that fat mass index, but not fat-free mass index, was positively correlated with rCGM in the medial prefrontal areas. CONCLUSION: This present study provides preliminary results suggesting that hypometabolism in the medial prefrontal areas is specifically associated with AD-related weight loss, and decrease in fat mass may have a key role.

PTPRQ as a potential biomarker for idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is caused by the accumulation of cerebrospinal fluid (CSF) and is characterized by gait disturbance, urinary incontinence, and dementia. iNPH dementia is treatable by shunt operation; however, since the cognitive symptoms of iNPH are often similar to those of other dementias, including Alzheimer's disease (AD), accurate diagnosis of iNPH is difficult. To overcome this problem, the identification of novel diagnostic markers to distinguish iNPH and AD is warranted. Using comparative proteomic analysis of CSF from patients with iNPH and AD, protein tyrosine phosphatase receptor type Q (PTPRQ) was identified as a candidate biomarker protein for discriminating iNPH from AD. ELISA analysis indicated that the PTPRQ concentration in the CSF was significantly higher in patients with iNPH compared with those with AD. In addition, the PTPRQ concentration in the CSF of non­responders to shunt operation (SNRs) tended to be relatively lower compared with that in the responders. PTPRQ may be a useful biomarker for discriminating between patients with iNPH and AD, and may be a potential companion biomarker to identify SNRs among patients with iNPH. Additional large­scale analysis may aid in understanding the novel aspects of iNPH.

An abnormal accumulation of fluorine-18-FDG PET in cytomegalovirus enteritis--a case report.

The source of a fever of unknown origin (FUO) and watery diarrhea in a 63-yr-old female with a history of disturbance of consciousness due to moyamoya disease was examined. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), colonoscopy, blood analysis, and determination of cytomegalovirus (CMV) antigenemia were performed. FDG was found to be accumulated in the wall of a dilated colon, and extended from the transverse to sigmoid colon. Colonoscopy revealed edematous, inflammatory, and punched out lesions in accordance with the areas of abnormal FDG uptake. A biopsy specimen showed the antibody of CMV in the colonic mucosa, and CMV antigenemia was detected by an immunohistochemical assay using a monoclonal antibody for CMV pp65 antigen. From these findings, we strongly suspected CMV enteritis.

Changes of neural activity correlate with the severity of cortical ischemia in patients with unilateral major cerebral artery occlusion.

BACKGROUND AND PURPOSE: In major cerebral arterial steno-occlusive diseases, there can be remarkably decreased hemodynamic reserve without marked neurological impairments. In such settings, it is not known whether the neural activity is well maintained or disturbed according to the severity of cerebral ischemia. The present study was therefore undertaken to examine the neural activity under mild cerebral ischemia resulting from major cerebral arterial occlusion. METHODS: Seven patients with minor neurological impairment as well as either unilateral internal carotid artery or middle cerebral artery occlusion were studied. The severity of the cortical ischemia was assessed by measuring regional cerebral blood flow (rCBF) with positron emission tomography. The change in neural activity in the ischemic brain was then evaluated by means of somatosensory evoked magnetic field with magnetoencephalography. RESULTS: The rCBF in the primary sensory area and the strength of the initial component of somatosensory evoked magnetic field (N20 m) were significantly reduced (P<0.01) and the second component (P30 m) was significantly augmented (P<0.05) in the lesioned cerebral hemisphere as compared with the nonlesioned hemisphere. The asymmetry indexes for N20 m were positively correlated (r=0.78) and those for P30 m were inversely correlated (r=-0.92) with asymmetry indexes for rCBF. CONCLUSIONS: In patients with either unilateral internal carotid artery or middle cerebral artery occlusion and minor neural impairments, there was a reduction of afferent signal and an augmentation of the secondary response of the neurons in the primary sensory area. This showed correlation with the severity of cortical ischemia.

Asymmetrical enhancement of middle-latency auditory evoked fields with aging.

We studied the effects of aging on middle-latency auditory evoked fields (P50m), and analyzed their interhemispheric differences. Magnetic responses following tone-burst stimuli to the right ear were measured in groups of 11 younger and 15 elderly subjects. The elderly subjects showed marked asymmetry in the P50m amplitudes. In the elderly group, the mean amplitude of the contralateral P50m was significantly larger (P<0.0005) than that of the ipsilateral P50m, while no asymmetry was shown in the younger group. The amplitude enlargement in the contralateral P50m showed significant correlation with age (R=0.60, P<0.005), while the ipsilateral P50m showed no correlation with age. These results suggest that the contralateral and ipsilateral auditory pathways are affected differently by ageing.

The effect of musical experience on hemispheric lateralization in musical feature processing.

Music consists of a variety of spectral and temporal features. Generally, brain processing of these features is reported as being right hemisphere dominant. However, there are contradicting results as to whether musical experience affects hemispheric laterality or not. In the present study, we investigated the effect of musical experience on hemispheric lateralization of musical feature processing using magnetoencephalography (MEG). Mismatch fields (MMFs) were measured from 8 musicians and 8 nonmusicians in oddball tasks with four different musical features, including pitch, chord, timbre and rhythm. Regardless of the features, the MMFs showed right-hemispheric dominance in nonmusicians, whereas musicians showed symmetrical MMF amplitudes in both hemispheres. The electrical activity around the auditory cortex to the MMFs also supported the right-hemispheric dominance in nonmusicians and bilateral activation in musicians. Voxel-based morphometry did not detect any group differences around the auditory cortices. These results suggest that musical training changes the hemispheric roles for musical feature processing in the pre-attentive stage, and this functional alteration can occur without apparent anatomical changes.