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Alterations to myelin may be a core pathological feature of neurodegenerative diseases. Although white matter microstructural differences have been described in Parkinson's disease (PD), it is unknown whether such differences include alterations of the brain’s myelin content. Thus, the objective of the current study is to measure and compare brain myelin content between PD patients and age-matched controls. In this cross-sectional study, 63 participants from the Longitudinal MRI in Parkinson's Disease study underwent brain MRI, Unified Parkinson's Disease Rating Scale (UPDRS) scoring, and cognitive asessments. Subjects were imaged with the mcDEPSOT (multi-component driven equilibrium single pulse observation of T1 and T2), a multicomponent relaxometry technique that quantifies longitudinal and transverse relaxation rates (R1 and R2, respectively) and the myelin water fraction (VFM), a surrogate for myelin content. A voxel-wise approach was used to compare R1, R2, and VFM measures between PD and control groups, and to evaluate relationships with age as well as disease duration, UPDRS scores, and daily levodopa equivalent dose. PD subjects had higher VFM than controls in frontal and temporal white matter and bilateral thalamus. Greater age was strongly associated with lower VFM in both groups, while an age-by-group interaction suggested a slower rate of VFM decline in the left putamen with aging in PD. Within the PD group, measures of disease severity, including UPDRS, daily levodopa equivalent dose, and disease duration, were observed to be related with myelin content in diffuse brain regions. The age-by-group interaction suggests that either PD or dopaminergic therapies allay observed age-related myelin changes. The relationships between VFM and disease severity measures suggests that VFM may provide a surrogate marker for microstructural changes related to Parkinson’s disease. [ABSTRACT FROM AUTHOR]

The definitive Alzheimer's disease (AD) diagnosis requires postmortem confirmation of neuropathological hallmarks-amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The advent of radiotracers for amyloid imaging presents an opportunity to investigate amyloid deposition in vivo. The C-Pittsburgh compound-B (PiB)-PET ligand remains the most widely studied to date; however, regional variations in C-PiB binding and the extent of agreement with neuropathological assessment have not been thoroughly investigated. Sojkova and colleagues [] reported variable agreement between CERAD-based neuropathologic diagnosis of AD lesions and mean cortical PiB, suggesting the need for a more direct quantification of regional Aβ in relation to in vivo imaging. In the present study, we extend these findings by examining the correspondence among regional C-PiB load, region-matched quantitative immunohistological assessments of Aβ and NFTs, and brain atrophy (MRI) in six older Baltimore Longitudinal Study of Aging participants who came to autopsy (imaging-autopsy interval range 0.2-2.4 years). The total number of Aβ plaques (6E10) and NFTs (PHF1) in paraffin sections from hippocampus, orbito-frontal cortex, anterior and posterior cingulate gyrus, precuneus and cerebellum was quantified using a technique guided by unbiased stereological principles. We report a general agreement between the regional measures of amyloid obtained via stereological assessment and imaging, with significant relationships evident for the anterior ( r = 0.83; p = 0.04) and posterior ( r = 0.94; p = 0.005) cingulate gyri, and the precuneus ( r = 0.94; p = 0.005). No associations were observed between C-PiB load and NFT count for any of the regions examined ( p > 0.2 in all regions), or between regional Aβ or NFT counts and corresponding brain volumes. The strong associations of PiB retention with region-matched, quantitative analyses of Aβ in postmortem tissue offer support for the validity of C-PiB-PET imaging as a method for evaluation of plaque burden in vivo. [ABSTRACT FROM AUTHOR]

Blood-based markers reflecting core pathological features of Alzheimer's disease (AD) in pre-symptomatic individuals are likely to accelerate the development of disease-modifying treatments. Our aim was to discover plasma proteins associated with brain amyloid-β (Aβ) burden in non-demented older individuals. We performed discovery-phase experiments using two dimensional gel electrophoresis (2DGE) and mass spectrometry-based proteomic analysis of plasma in combination with 11C-PiB PET imaging of the brain in samples collected 10 years prior to the PET scans. Confirmatory studies used ELISA assays in a separate set of blood samples obtained within a year of the PET scans. We observed that a panel of 18 2DGE plasma protein spots effectively discriminated between individuals with high and low brain Aβ. Mass spectrometry identified these proteins, many of which have established roles in Aβ clearance, including a strong signal from apolipoprotein-E (ApoE). In validation-phase studies, we observed a strong association between plasma ApoE concentration and Aβ burden in the medial temporal lobe. Targeted voxel-based analysis localized this association to the hippocampus and entorhinal cortex. APOE ε4 carriers also showed greater Aβ levels in several brain regions relative to ε4 non-carriers. These results suggest that both peripheral concentration of ApoE protein and APOE genotype are related to early neuropathological changes in brain regions vulnerable to AD pathology even in the non-demented elderly. Our strategy combining proteomics with in vivo brain amyloid imaging holds promise for the discovery of biologically relevant peripheral markers in those at risk for AD. [ABSTRACT FROM AUTHOR]

Abstract: Amyloid-β plaques (Aβ) are a hallmark of Alzheimer''s disease (AD), begin deposition decades before the incipient disease, and are thought to be associated with neuronal loss, brain atrophy and cognitive impairment. We examine associations between 11C-PiB-PET measurement of Aβ burden and brain volume changes in the preceding years in 57 non-demented individuals (age 64–86; M =78.7). Participants were prospectively followed through the Baltimore Longitudinal Study of Aging, with up to 10 consecutive MRI scans (M =8.1) and an 11C-PiB scan approximately 10 years after the initial MRI. Linear mixed effects models were used to determine whether mean cortical 11C-PiB distribution volume ratios, estimated by fitting a reference tissue model to the measured time activity curves, were associated with longitudinal regional brain volume changes of the whole brain, ventricular CSF, frontal, temporal, parietal, and occipital white and gray matter, the hippocampus, orbito-frontal cortex, and the precuneus. Despite significant longitudinal declines in the volumes of all investigated regions (p <0.05), no associations were detected between current Aβ burden and regional brain volume decline trajectories in the preceding years, nor did the regional volume trajectories differ between those with highest and lowest Aβ burden. Consistent with a threshold model of disease, our findings suggest that Aβ load does not seem to affect brain volume changes in individuals without dementia. [Copyright &y& Elsevier]

Background: In demented older adults, in vivo amyloid imaging shows agreement with diagnostic neuropathologic assessment of β-amyloid (Aβ). However, the extent of agreement in nondemented older adults remains unclear., Objective: To compare Aβ quantified using in vivo carbon 11-labeled Pittsburgh Compound B positron emission tomography and postmortem neuropathologic assessment of Aβ in older adults., Design: Case series., Setting: Community-dwelling older adults who came to autopsy., Participants: Five nondemented and 1 demented participant from the Baltimore Longitudinal Study of Aging., Main Outcome Measure: Agreement between the mean cortical distribution volume ratio and the Consortium to Establish a Registry for AD (CERAD) neuritic plaque (NP) score used for pathologic diagnosis of Alzheimer disease., Results: Of the 6 participants, 4 had moderate NPs, 2 had sparse or no detectable NPs, and 3 had microscopic findings of cerebral amyloid angiopathy at autopsy. On in vivo imaging, the mean cortical distribution volume ratio ranged from 0.96 to 1.59. Although there was agreement between in vivo amyloid imaging and CERAD NP scores in participants with either high or negligible Aβ levels in vivo, only limited agreement was observed among those with intermediate levels of Aβ. The best overall agreement was achieved at a distribution volume ratio of 1.2., Conclusions: In older adults, variable agreement between in vivo imaging and CERAD NP score was observed. The limited agreement may, in part, reflect differences in typical measurements of Aβ using imaging compared with the CERAD neuropathologic protocol. Direct quantification of regional Aβ in relation to in vivo imaging is necessary to further enhance our understanding of the imaging-pathologic assessment correlation.