Cross-sectional and longitudinal associations between total and regional white matter hyperintensity volume and cognitive and motor function in Parkinson's disease.

BACKGROUND: White matter hyperintensities (WMH) are frequently observed on T2-weighted brain magnetic resonance imaging studies of healthy older adults and have been linked with impairments in balance, gait, and cognition. Nonetheless, few studies have investigated the longitudinal effects of comorbid WMH on cognition and motor function in Parkinson's disease. METHODS: The Lesion Segmentation Tool for Statistical Parametric Mapping was used to obtain total lesion volume and map regional WMH probabilities in 29 PD and 42 control participants at two study visits 18 months apart. Both cross-sectional and longitudinal comparisons were made between composite scores in the domains of executive function, memory, and language, and Unified Parkinson's Disease Rating Scale (UPDRS) scores. RESULTS: We found no difference between disease and control groups in total WMH volume or progression during the study. Greater regional and global WMH at baseline was more strongly associated with lower executive function in PD subjects than in controls. Increased regional WMH was also more strongly associated with impaired memory performance in PD relative to controls. Longitudinally, no associations between cognitive change and total or regional WMH progression were detected in either group. A positive relationship between baseline regional WMH and total UPDRS scores was present in the control group, but not PD. However, greater WMH increase was associated with a greater increase in UPDRS motor sub-scores in PD. CONCLUSIONS: These findings suggest that although PD patients do not experience greater mean WMH load than normal aged adults, comorbid WMH do exacerbate cognitive and motor symptoms in PD.

Arterial spin labeling reveals relationships between resting cerebral perfusion and motor learning in Parkinson's disease.

Parkinson's disease (PD) is an age-related neurodegenerative disease that produces changes in movement, cognition, sleep, and autonomic function. Motor learning involves acquisition of new motor skills through practice, and is affected by PD. The purpose of the present study was to evaluate regional differences in resting cerebral blood flow (rCBF), measured using arterial spin labeling (ASL) MRI, during a finger-typing task of motor skill acquisition in PD patients compared to age- and gender-matched controls. Voxel-wise multiple linear regression models were used to examine the relationship between rCBF and several task variables, including initial speed, proficiency gain, and accuracy. In these models, a task-by-disease group interaction term was included to investigate where the relationship between rCBF and task performance was influenced by PD. At baseline, perfusion was lower in PD subjects than controls in the right occipital cortex. The task-by-disease group interaction for initial speed was significantly related to rCBF (p < 0.05, corrected) in several brain regions involved in motor learning, including the occipital, parietal, and temporal cortices, cerebellum, anterior cingulate, and the superior and middle frontal gyri. In these regions, PD patients showed higher rCBF, and controls lower rCBF, with improved performance. Within the control group, proficiency gain over 12 typing trials was related to greater rCBF in cerebellar, occipital, and temporal cortices. These results suggest that higher rCBF within networks involved in motor learning enable PD patients to compensate for disease-related deficits.

Longitudinal white matter microstructural change in Parkinson's disease.

Postmortem studies of Parkinson's disease (PD) suggest that Lewy body pathology accumulates in a predictable topographical sequence, beginning in the olfactory bulb, followed by caudal brainstem, substantia nigra, limbic cortex, and neocortex. Diffusion-weighted imaging (DWI) is sensitive, if not specific, to early disease-related white matter (WM) change in a variety of traumatic and degenerative brain diseases. Although numerous cross-sectional studies have reported DWI differences in cerebral WM in PD, only a few longitudinal studies have investigated whether DWI change exceeds that of normal aging or coincides with regional Lewy body accumulation. This study mapped regional differences in the rate of DWI-based microstructural change between 29 PD patients and 43 age-matched controls over 18 months. Iterative within- and between-subject tensor-based registration was completed on motion- and eddy current-corrected DWI images, then baseline versus follow-up difference maps of fractional anisotropy, mean, radial, and axial diffusivity were analyzed in the Biological Parametric Mapping toolbox for MATLAB. This analysis showed that PD patients had a greater decline in WM integrity in the rostral brainstem, caudal subcortical WM, and cerebellar peduncles, compared with controls. In addition, patients with unilateral clinical signs at baseline experienced a greater rate of WM change over the 18-month study than patients with bilateral signs. These findings suggest that rate of WM microstructural change in PD exceeds that of normal aging and is maximal during early stage disease. In addition, the neuroanatomic locations (rostral brainstem and subcortical WM) of accelerated WM change fit with current theories of topographic disease progression.

Alterations of Myelin Content in Parkinson's Disease: A Cross-Sectional Neuroimaging Study.

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.

Voxelwise Relationships Between Distribution Volume Ratio and Cerebral Blood Flow: Implications for Analysis of ß-Amyloid Images.

UNLABELLED: Quantification of ß-amyloid (Aß) in vivo is often accomplished using the distribution volume ratio (DVR), based on a simplified reference tissue model. We investigated the local relationships between DVR and cerebral blood flow (CBF), as well as relative CBF (R1), in nondemented older adults. METHODS: Fifty-five nondemented participants (mean age, 78.5 y) in the Baltimore Longitudinal Study of Aging underwent (15)O-H2O PET CBF and dynamic (11)C-PiB PET. (15)O-H2O PET images were normalized and smoothed using SPM. A simplified reference tissue model with linear regression and spatial constraints was used to generate parametric DVR images. The DVR images were regressed on CBF images on a voxel-by-voxel basis using robust biologic parametric mapping, adjusting for age and sex (false discovery rate, P = 0.05; spatial extent, 50 voxels). DVR images were also regressed on R1 images, a measure of the transport rate constant from vascular space to tissue. All analyses were performed on the entire sample, and on high and low tertiles of mean cortical DVR. RESULTS: Voxel-based analyses showed that increased DVR is associated with increased CBF in the frontal, parietal, temporal, and occipital cortices. However, this association appears to spare regions that typically show early Aß deposition. A more robust relationship between DVR and CBF was observed in the lower tertile of DVR, that is, negligible cortical Aß load, compared with the upper tertile of cortical DVR and Aß load. The spatial distributions of the DVR-CBF and DVR-R1 correlations showed similar patterns. No reliable negative voxelwise relationships between DVR and CBF or R1 were observed. CONCLUSION: Robust associations between DVR and CBF at negligible Aß levels, together with similar spatial distributions of DVR-CBF and DVR-R1 correlations, suggest that regional distribution of DVR reflects blood flow and tracer influx rather than pattern of Aß deposition in those with minimal Aß load. DVR-CBF associations in individuals with a higher DVR are more likely to reflect true associations between patterns of Aß deposition and CBF or neural activity. These findings have important implications for analysis and interpretation of voxelwise correlations with external variables in individuals with varying amounts of Aß load.

Anterior cingulate dopamine turnover and behavior change in Parkinson's disease.

Subtle cognitive and behavioral changes are common in early Parkinson's disease. The cause of these symptoms is probably multifactorial but may in part be related to extra-striatal dopamine levels. 6-[(18) F]-Fluoro-L-dopa (FDOPA) positron emission tomography has been widely used to quantify dopamine metabolism in the brain; the most frequently measured kinetic parameter is the tissue uptake rate constant, Ki. However, estimates of dopamine turnover, which also account for the small rate of FDOPA loss from areas of specific trapping, may be more sensitive than Ki for early disease-related changes in dopamine biosynthesis. The purpose of the present study was to compare effective distribution volume ratio (eDVR), a metric for dopamine turnover, to cognitive and behavioral measures in Parkinson's patients. We chose to focus the investigation on anterior cingulate cortex, which shows highest FDOPA uptake within frontal regions and has known roles in executive function. Fifteen non-demented early-stage PD patients were pretreated with carbidopa and tolcapone, a central catechol-O-methyl transferase (COMT) inhibitor, and then underwent extended imaging with FDOPA PET. Anterior cingulate eDVR was compared with composite scores for language, memory, and executive function measured by neuropsychological testing, and behavior change measured using two informant-based questionnaires, the Cambridge Behavioral Inventory and the Behavior Rating Inventory of Executive Function-Adult Version. Lower mean eDVR (thus higher dopamine turnover) in anterior cingulate cortex was related to lower (more impaired) behavior scores. We conclude that subtle changes in anterior cingulate dopamine metabolism may contribute to dysexecutive behaviors in Parkinson's disease.

Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden.

The development of amyloid imaging compounds has allowed in vivo imaging of amyloid deposition. In this study, we examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue ((11)C-PiB) positron emission tomography data from the Baltimore Longitudinal Study of Aging. We used a new methodology that allowed us to approximate spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Our results are consistent with patterns of progression known from autopsy studies, with frontal and precuneus regions affected early and occipital and sensorimotor cortices affected later in disease progression--here, disease progression means lower-to-higher total amyloid burden. Furthermore, we divided participants into subgroups based on longitudinal change in memory performance, and demonstrated significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. Our results indicate that the spatial pattern of amyloid deposition is related to cognitive performance and may be more informative than a biomarker reflecting total amyloid burden, the use of which is the current practice. This finding has broad implications for our understanding of the relationship between cognitive decline/resilience and amyloid deposition, as well as for the use of amyloid imaging as a biomarker in research and clinical applications.

Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype.

BACKGROUND: The rs3818361 single nucleotide polymorphism in complement component (3b/4b) receptor-1 (CR1) is associated with increased risk of Alzheimer's disease (AD). Although this novel variant is associated with a small effect size and is unlikely to be useful as a predictor of AD risk, it might provide insights into AD pathogenesis. We examined the association between rs3818361 and brain amyloid deposition in nondemented older individuals. METHODS: We used (11)C-Pittsburgh Compound-B positron emission tomography to quantify brain amyloid burden in 57 nondemented older individuals (mean age 78.5 years) in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging. In a replication study, we analyzed (11)C-Pittsburgh Compound-B positron emission tomography data from 22 cognitively normal older individuals (mean age 77.1 years) in the Alzheimer's Disease Neuroimaging Initiative dataset. RESULTS: Risk allele carriers of rs3818361 have lower brain amyloid burden relative to noncarriers. There is a strikingly greater variability in brain amyloid deposition in the noncarrier group relative to risk carriers, an effect explained partly by APOE genotype. In noncarriers of the CR1 risk allele, APOE ε4 individuals showed significantly higher brain amyloid burden relative to APOE ε4 noncarriers. We also independently replicate our observation of lower brain amyloid burden in risk allele carriers of rs3818361 in the Alzheimer's Disease Neuroimaging Initiative sample. CONCLUSIONS: Our findings suggest complex mechanisms underlying the interaction of CR1, APOE, and brain amyloid pathways in AD. Our results are relevant to treatments targeting brain Aß in nondemented individuals at risk for AD and suggest that clinical outcomes of such treatments might be influenced by complex gene-gene interactions.

Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques.

The definitive Alzheimer's disease (AD) diagnosis requires postmortem confirmation of neuropathological hallmarks-amyloid-ß (Aß) plaques and neurofibrillary tangles (NFTs). The advent of radiotracers for amyloid imaging presents an opportunity to investigate amyloid deposition in vivo. The (11)C-Pittsburgh compound-B (PiB)-PET ligand remains the most widely studied to date; however, regional variations in (11)C-PiB binding and the extent of agreement with neuropathological assessment have not been thoroughly investigated. Sojkova and colleagues [35] 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 Aß in relation to in vivo imaging. In the present study, we extend these findings by examining the correspondence among regional (11)C-PiB load, region-matched quantitative immunohistological assessments of Aß 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 Aß 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 (11)C-PiB load and NFT count for any of the regions examined (p > 0.2 in all regions), or between regional Aß or NFT counts and corresponding brain volumes. The strong associations of PiB retention with region-matched, quantitative analyses of Aß in postmortem tissue offer support for the validity of (11)C-PiB-PET imaging as a method for evaluation of plaque burden in vivo.

Patterns of regional cerebral blood flow associated with low hemoglobin in the Baltimore Longitudinal Study of Aging.

BACKGROUND: Anemia has been associated with elevated cerebral blood flow (CBF) in animal models and certain clinical conditions (eg, renal disease), but whether hemoglobin level variations across a relatively normal range are associated with local or diffuse CBF changes is unclear. We investigated whether lower hemoglobin is associated with regional increases in relative CBF in older individuals, and if these increases occur in watershed regions. METHODS: Seventy-four older nondemented adults underwent serial (15)O water positron emission tomography scans. Voxel-based analysis was used to investigate regional relative CBF patterns in association with hemoglobin level and in individuals with and without anemia. Analyses of cross-sectional relations between regional CBF and anemia were performed separately at two time points, 2 years apart, to identify replicable patterns of associations. RESULTS: Restricting results to associations replicated across two cross-sectional analyses, lower hemoglobin was associated with higher relative CBF within the middle/inferior frontal, occipital, precuneus, and cerebellar regions. In addition, individuals with anemia (n = 15) showed higher relative CBF in superior frontal, middle temporal, hippocampal, and gyrus rectus regions than those without anemia. In some regions (right superior temporal gyrus, left inferior frontal gyrus, midline cuneus, and right precuneus); however, lower hemoglobin was associated with lower relative CBF. CONCLUSIONS: In nondemented individuals, lower hemoglobin is associated with elevated relative CBF in specific cortical areas but reduced CBF in other areas. Whether this association between anemia and CBF in the absence of chronic diseases and in a normal physiologic range is related to clinical endpoints warrants further study.

Baseline cardiovascular risk predicts subsequent changes in resting brain function.

BACKGROUND AND PURPOSE: The Framingham Heart Study group cardiovascular disease risk profile (FCRP) score was used to assess the relationship between baseline cardiovascular risk and subsequent changes in resting state cerebral blood flow (CBF) in cognitively normal older participants from the Baltimore Longitudinal Study of Aging. METHODS: Ninty-seven cognitively normal participants underwent annual resting-state positron emission tomography scans at baseline and over a period of up to 8 years (mean interval, 7.4 years). Images quantifying voxel-wise longitudinal rates of CBF change were calculated and used to examine the relationship between baseline FCRP score and changes over time in regional CBF. Individual components of the FCRP score (age, cholesterol, blood pressure, smoking status, and type 2 diabetes) were also correlated with changes in regional CBF to examine the independent contributions of each component to the overall pattern of change. RESULTS: Higher baseline FCRP scores were associated with accelerated longitudinal decline in CBF in orbitofrontal, medial frontal/anterior cingulate, insular, precuneus, and brain stem regions. Of the components that comprise the FCRP score, higher diastolic blood pressure and diabetes were associated independently with greater decline in the medial frontal/anterior cingulate and insular regions, respectively. CONCLUSIONS: Baseline cardiovascular risk factors are associated with greater rates of decline in resting state regional brain function. The regions showing accelerated decline participate in higher-order cognitive processes and are also vulnerable to age-related neuropathology. These results, in conjunction with other studies, encourage early treatment of cardiovascular risk factors in older individuals.

Relative equilibrium plot improves graphical analysis and allows bias correction of standardized uptake value ratio in quantitative 11C-PiB PET studies.

UNLABELLED: Both the standardized uptake value ratio (SUVR) and the Logan plot result in biased distribution volume ratios (DVRs) in ligand-receptor dynamic PET studies. The objective of this study was to use a recently developed relative equilibrium-based graphical (RE) plot method to improve and simplify the 2 commonly used methods for quantification of (11)C-Pittsburgh compound B ((11)C-PiB) PET. METHODS: The overestimation of DVR in SUVR was analyzed theoretically using the Logan and the RE plots. A bias-corrected SUVR (bcSUVR) was derived from the RE plot. Seventy-eight (11)C-PiB dynamic PET scans (66 from controls and 12 from participants with mild cognitive impaired [MCI] from the Baltimore Longitudinal Study of Aging) were acquired over 90 min. Regions of interest (ROIs) were defined on coregistered MR images. Both the ROI and the pixelwise time-activity curves were used to evaluate the estimates of DVR. DVRs obtained using the Logan plot applied to ROI time-activity curves were used as a reference for comparison of DVR estimates. RESULTS: Results from the theoretic analysis were confirmed by human studies. ROI estimates from the RE plot and the bcSUVR were nearly identical to those from the Logan plot with ROI time-activity curves. In contrast, ROI estimates from DVR images in frontal, temporal, parietal, and cingulate regions and the striatum were underestimated by the Logan plot (controls, 4%-12%; MCI, 9%-16%) and overestimated by the SUVR (controls, 8%-16%; MCI, 16%-24%). This bias was higher in the MCI group than in controls (P < 0.01) but was not present when data were analyzed using either the RE plot or the bcSUVR. CONCLUSION: The RE plot improves pixelwise quantification of (11)C-PiB dynamic PET, compared with the conventional Logan plot. The bcSUVR results in lower bias and higher consistency of DVR estimates than of SUVR. The RE plot and the bcSUVR are practical quantitative approaches that improve the analysis of (11)C-PiB studies.

Longitudinal patterns of ß-amyloid deposition in nondemented older adults.

BACKGROUND: High levels of ß-amyloid (Aß) characterize Alzheimer disease. OBJECTIVE: To investigate whether longitudinal changes in Aß deposition can be detected in vivo in older adults without dementia (hereafter referred to as nondemented). DESIGN: Prospective study. SETTING: Community-dwelling older adults. PARTICIPANTS: Twenty-four nondemented participants (4 with a baseline Clinical Dementia Rating Scale score of 0.5; mean [SD] age, 79.2 [8.1] years) in the Baltimore Longitudinal Study of Aging underwent serial carbon 11-labeled Pittsburgh Compound B-positron emission tomography ([(11)C]PiB-PET) (follow-up at a mean [SD] of 1.5 [0.5] years), with 5 participants undergoing a third [(11)C]PiB-PET examination. MAIN OUTCOME MEASURES: Annual changes in distribution volume ratio (DVR) were evaluated using a global index of cortical DVR (cDVR) and region-of-interest analyses. Given the variability of cDVR at the initial PiB-PET, annual changes in cDVR in those with minimal vs those with elevated initial cDVR were compared. RESULTS: In nondemented older adults, annual increase in [(11)C]PiB retention is 0.011 DVR per year (0.9%; P = .01), which localizes to the prefrontal, parietal, lateral temporal, occipital, and anterior and posterior cingulate cortices. Annual change in cDVR is greater in older adults with elevated cDVR than in those with a minimal initial cDVR (P = .006). CONCLUSIONS: Fibrillar Aß detected by [(11)C]PiB-PET increases over time even in nondemented older adults. Individuals with higher initial [(11)C]PiB retention have greater rates of Aß deposition, providing evidence of differential rates of Aß deposition. Moreover, regional vulnerabilities to Aß deposition allow for more targeted investigation of early Aß changes.

In vivo fibrillar beta-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults.

BACKGROUND: In demented older adults, in vivo amyloid imaging shows agreement with diagnostic neuropathologic assessment of ß-amyloid (Aß). However, the extent of agreement in nondemented older adults remains unclear. OBJECTIVE: To compare Aß quantified using in vivo carbon 11-labeled Pittsburgh Compound B positron emission tomography and postmortem neuropathologic assessment of Aß 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 Aß levels in vivo, only limited agreement was observed among those with intermediate levels of Aß. 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 Aß using imaging compared with the CERAD neuropathologic protocol. Direct quantification of regional Aß in relation to in vivo imaging is necessary to further enhance our understanding of the imaging-pathologic assessment correlation.

Amyloid imaging and memory change for prediction of cognitive impairment.

PET radiotracers for in vivo measurement of ß-amyloid (Aß) deposition throughout the brain are contributing to early detection of the neuropathology associated with Alzheimer's disease and enhancing prediction of individuals most likely to develop cognitive impairment and dementia. However, the fact that 30 to 50% of cognitively normal older adults have varying but detectable levels of Aß poses challenges and opportunities in using amyloid imaging in research and clinical applications. In this review, we summarize studies of the relationship between Aß burden and cognitive status in impaired and unimpaired individuals and the relationship between Aß burden and cognitive function. We conclude by operationalizing the way in which information on imaging-assessed Aß burden and cognitive performance can be used jointly to improve prediction of clinical outcomes, to enhance understanding of the role of Aß deposition in cognitive impairment, and to identify factors that promote cognitive resilience in the presence of Aß.

Lack of association between 11C-PiB and longitudinal brain atrophy in non-demented older individuals.

Amyloid-ß plaques (Aß) 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 (11)C-PiB-PET measurement of Aß 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 (11)C-PiB scan approximately 10 years after the initial MRI. Linear mixed effects models were used to determine whether mean cortical (11)C-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 Aß burden and regional brain volume decline trajectories in the preceding years, nor did the regional volume trajectories differ between those with highest and lowest Aß burden. Consistent with a threshold model of disease, our findings suggest that Aß load does not seem to affect brain volume changes in individuals without dementia.

Proteome-based plasma markers of brain amyloid-ß deposition in non-demented older individuals.

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-ß (Aß) 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 Aß. Mass spectrometry identified these proteins, many of which have established roles in Aß clearance, including a strong signal from apolipoprotein-E (ApoE). In validation-phase studies, we observed a strong association between plasma ApoE concentration and Aß 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 Aß 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.

Intima-media thickness and regional cerebral blood flow in older adults.

BACKGROUND AND PURPOSE: The relationship between the thickness of the carotid intima (IMT) and brain function remains unclear in those without clinical manifestations of cerebrovascular disease. Understanding the neural correlates of this vascular measure is important in view of emerging evidence linking poorer cognitive performance with increased IMT in individuals without clinical cerebrovascular disease. METHODS: Seventy-three participants in the Baltimore Longitudinal Study of Aging (70.9 years; SD, 7.3) were evaluated with carotid artery ultrasound and resting [(15)O]H(2)O positron emission tomography. RESULTS: After adjusting for age, gender, and gray and white matter volumes in the regions where IMT is related to regional cerebral blood flow (rCBF), we found that higher IMT was associated with lower rCBF in lingual, inferior occipital, and superior temporal regions. Higher IMT was also associated with higher rCBF in medial frontal gyrus, putamen, and hippocampal-uncal regions (P=0.001). Whereas women had lower IMT (P=0.01) and mean arterial pressure (P=0.05) than men, they showed more robust associations between IMT and rCBF. The relationship between IMT and rCBF was only minimally affected by additional adjustment for mean arterial pressure. CONCLUSIONS: IMT is related to patterns of resting rCBF in older adults without clinical manifestations of cerebrovascular disease, suggesting that there are regional differences in CBF that are associated with subclinical vascular disease.

Longitudinal cerebral blood flow and amyloid deposition: an emerging pattern?

UNLABELLED: Although cerebral amyloid deposition may precede cognitive impairment by decades, the relationship between amyloid deposition and longitudinal change in neuronal function has not, to our knowledge, been studied. The aim of this article was to determine whether individuals without dementia with high and low amyloid burden show different patterns of longitudinal regional cerebral blood flow (rCBF) changes in the years preceding measurement of amyloid deposition. METHODS: Twenty-eight participants without dementia (mean age+/-SD, 82.5+/-4.8 y; 6 mildly impaired) from the Baltimore Longitudinal Study of Aging underwent yearly resting-state (15)O-H(2)O PET scans for up to 8 y. (11)C-PIB images of amyloid deposition were acquired on average 10.8+/-0.8 y after the first CBF scan. (11)C-PIB distribution volume ratios of regions of interest were estimated by fitting a reference-tissue model to the measured time-activity curves. On the basis of mean cortical distribution volume ratios, participants were divided into groups with high or low (11)C-PIB retention. Differences in longitudinal rCBF changes between high- and low-(11)C-PIB groups were investigated by voxel-based analysis. RESULTS: Longitudinal rCBF changes differed significantly between high- (n=10) and low- (n=18) (11)C-PIB groups (P

Does asymmetric basal ganglia or thalamic activation aid in seizure foci lateralization on ictal SPECT studies?

UNLABELLED: Basal ganglia or thalamic activation has been reported in ictal SPECT studies of patients with intractable epilepsy. We hypothesized that lateralization of activation of these subcortical structures may aid in the lateralization of seizure foci in patients in whom the cortical focus is subtle or equivocal. METHODS: This was a retrospective analysis of 72 ictal (99m)Tc-ethylcysteinate dimer SPECT studies in 43 patients with intractable epilepsy in whom seizure laterality could be eventually determined. All patients underwent video-electroencephalography (EEG) monitoring, MRI, and one or more ictal SPECT scans as well as an interictal SPECT scan. Intracranial electrode EEG monitoring and surgery were performed as clinically indicated. Ictal and interictal studies were coregistered with patients' MRI scans using automated software, and ictal minus interictal subtraction images were obtained. The presence of asymmetric basal ganglia or thalamic activation was determined by 2 experienced observers who were unaware of clinical information. The final seizure focus was determined by surgical cure in 37 patients. In patients in whom surgery was not indicated or initial surgery was performed at another institution (n = 6), a consistent focus detected by intracranial electrode monitoring or repeated stereotypical seizures all originating from the same site on video-surface EEG monitoring was considered to indicate the final seizure focus. RESULTS: Thirty-five patients had neocortical seizures and 8 had mesial temporal lobe seizures. Asymmetric basal ganglia activation was seen in 22 (30.6%) studies. This activation was ipsilateral to the final determined seizure focus in 17 of 22 of these studies (77.3%) and contralateral in 5 of 22 (21.7%). Asymmetric thalamic activation was seen in 15 studies (20.8%), of which 12 of 15 (80%) were ipsilateral to the final seizure focus, whereas 3 of 15 (20%) were contralateral. In 3 of 5 studies with contralateral basal ganglia activation and 1 of 3 studies with contralateral thalamic activation, the SPECT study as a whole was found to be falsely localizing. In another 2 cases of contralateral subcortical activation, the SPECT study as a whole was considered nonlocalizing. Worse outcome was not observed in patients with false ictal SPECT subcortical lateralization; however, the presence of asymmetric subcortical uptake, regardless of relationship to seizure focus, was associated with decreased incidence of seizures at 1 y after surgery. CONCLUSION: Although asymmetric basal ganglia or thalamic activation is common, it is rarely the sole indicator of seizure localization. However, it may be a useful confirmatory sign in subtle cases of cortical localization. In cases of false ictal SPECT subcortical lateralization, the basal ganglia appear to follow cortical activation pattern. Furthermore, there appears to be a correlation between lateralizing uptake in subcortical structures on ictal SPECT and postsurgical outcome in intractable epilepsy patients.