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1.  Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: A multimodal imaging investigation 
NeuroImage : Clinical  2014;4:604-614.
Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (Aβ+), amyloid indeterminate (Aβi), or amyloid negative (Aβ−) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ− in all three ROIs and in Aβi compared to Aβ− in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses showing that cognitive function in these participants is not associated with any of the four DTI metrics, the present results suggest an early relationship between PiB and DTI, which may be a meaningful indicator of the initiating or compensatory mechanisms of AD prior to cognitive decline.
Graphical abstract
•Study cohort of preclinical subjects (N = 139) at risk for Alzheimer's disease•Examination of four DTI metrics in three groups based on global amyloid load•Greater amyloid load was associated with higher fractional anisotropy.•Diffusivity was negatively associated with amyloid in fronto-lateral gray matter.•DTI metrics were not correlated with cognition at this early disease stage.
PMCID: PMC4053642  PMID: 24936411
DTI, Diffusion Tensor Imaging; PIB, Pittsburgh compound B; WRAP, Wisconsin Registry for Alzheimer's Prevention; FA, fractional anisotropy; MD, mean diffusivity; Da, axial diffusivity; Dr, radial diffusivity; APOE4, apolipoprotein E gene ε4; FH, (parental) family history; WM, white matter; GM, gray matter; Aβ+, amyloid positive; Aβi, amyloid indeterminate; Aβ−, amyloid negative; SPM, Statistical Parametric Mapping; FSL, FMRIB Software Library; PRELUDE, phase region expanding labeler for unwrapping discrete estimates; FUGUE, FMRIB's utility for geometrically unwarping EPIs; BET, Brain Extraction Tool; DTI-TK, Diffusion Tensor Imaging Toolkit; HARDI, high angular resolution diffusion imaging; DVR, distribution volume ratio; ICBM, International Consortium for Brain Mapping; ANTs, Advanced Normalization Tools; Cingulum–CC, cingulum adjacent to corpus callosum; Cingulum–HC, hippocampal cingulum (projecting to medial temporal lobe); PCC, posterior cingulate cortex; RAVLT, Rey Auditory Verbal Learning Test; TMT, Trail Making Test; ANCOVA, Analysis of Covariance; FWE, family wise error; WASI, Wechsler Abbreviated Scale of Intelligence; WRAT, Wide Range Achievement Test; Alzheimer's disease; Amyloid imaging; AD risk; White matter
2.  Low cerebral blood flow is associated with lower memory function in metabolic syndrome 
Obesity (Silver Spring, Md.)  2013;21(7):1313-1320.
Metabolic syndrome (MetS)—a cluster of cardiovascular risk factors—is linked with cognitive decline and dementia. However, the brain changes underlying this link are presently unknown. In this study, we tested the relationship between MetS, cerebral blood flow (CBF), white matter hyperintensity (WMH) burden and gray matter (GM) volume in cognitively healthy late middleaged adults. Additionally, we assessed the extent to which MetS was associated with cognitive performance.
Methods and Results
Late middle-aged adults from the Wisconsin Registry for Alzheimer’s Prevention (N=69, mean age=60.4 yrs) underwent a fasting blood draw, arterial spin labeling perfusion MRI, T1-weighted MRI, T2FLAIR MRI, and neuropsychological testing. MetS was defined as abnormalities on 3 or more factors, including: abdominal obesity, triglycerides, HDL-cholesterol, blood pressure, and fasting glucose.
Mean GM CBF was 15% lower in MetS compared to controls. Voxel-wise image analysis indicated that the MetS group had lower CBF across a large portion of the cortical surface, with the exception of medial and inferior parts of the occipital and temporal lobes. The MetS group also had lower immediate memory function; a mediation analysis indicated this relationship was partially mediated by CBF. Among the MetS factors, abdominal obesity and elevated triglycerides were most strongly associated with lower CBF.
The results underscore the importance of reducing the number of cardiovascular risk factors for maintaining CBF and cognition in an aging population.
PMCID: PMC3742665  PMID: 23687103
cerebral blood flow; brain; magnetic resonance imaging; metabolic syndrome; cognitive function
3.  18F-DOPA PET with and without MRI fusion, a receiver operator characteristics comparison 
This study is a retrospective analysis of the diagnostic accuracy of FDOPA PET with MRI fusion to FDOPA PET without MRI fusion. Clinical FDOPA PET scans obtained between 2000 and 2008 at the University of Wisconsin Hospital and Clinics were assessed using measures derived from regions of interest (ROI) generated with fused MRI (fused group) and again with ROIs derived solely from PET data (non-fused groups). The ROIs were used to calculate ratios (Striatum/Occipital cortex, Striatum/Cerebellum) pertinent to Parkinson’s disease (PD) pathology. The clinical records were assessed for demographic data, follow-up length, and diagnosis. Receiver Operator Characteristics with area under the curve (AUC) measures were calculated and compared using confidence intervals and hypothesis testing. 27 patients had FDOPA PET with median clinical follow-up of 4 years. Of these, 17 patients had FDOPA PET with a fusible MR image. Seven of the 27 had a non-PD movement disorder. AUCs for the ratio measures ranged from 0.97-1.0 (fused), 0.73-0.83 (non-fused), and 0.63-0.82 (matched non-fused). The fused images had improved accuracy compared to the matched non-fused and all non-fused groups for the striatum to occipital group (p=0.04, p=0.03), while the striatum to cerebellum ratio had improvement over the non-fused all group (p=0.041). MR fusion to FDOPA PET improves the accuracy of at least some measures (Striatum/Occiput, Striatum/Cerebellum) in the diagnosis of PD.
PMCID: PMC3484423  PMID: 23145363
18F-Fluorodopa; positron emission tomography; image fusion; receiver operator characteristics; Parkinson’s
4.  A longitudinal study of motor performance and striatal [18F]fluorodopa uptake in Parkinson's disease 
Brain imaging and behavior  2011;5(3):203-211.
Although [18F]fluoro-L-dopa [FDOPA] positron emission tomography (PET) has been used as a surrogate outcome measure in Parkinson's disease therapeutic trials, this biomarker has not been proven to reflect clinical status longitudinally. We completed a retrospective analysis of relationships between computerized sampling of motor performance, FDOPA PET, and clinical outcome scales, repeated over 4 years, in 26 Parkinson's disease (PD) patients and 11 healthy controls. Mixed effects analyses showed that movement time and tongue strength best differentiated PD from control subjects. In the treated PD cohort, motor performance measures changed gradually in contrast to a steady decline in striatal FDOPA uptake. Prolonged reaction and movement time were related to lower caudate nucleus FDOPA uptake, and abnormalities in hand fine force control were related to mean striatal FDOPA uptake. These findings provide evidence that regional loss of nigrostriatal inputs to frontostriatal networks affects specific aspects of motor function.
PMCID: PMC3150388  PMID: 21556744
Fluorodopa; motor control; Parkinson's disease; positron emission tomography; ageing; Tongue/*physiopathology; Facial Muscles/*physiopathology
5.  Rate of 6-[18F]fluoro-L-dopa uptake decline in striatal subregions in Parkinson’s disease 
Using both a volume of interest (VOI) and whole brain voxel-wise approach, we compared rates of decline of 6-L-[18F]-fluorodopa (FDOPA) positron emission tomography (PET) uptake ipsilateral (IL) and contralateral (CL) to the initially symptomatic limbs over 4.5 years in 26 subjects with Parkinson’s disease (PD) and 11 controls. The VOI approach used six subregions: Head/body of caudate nucleus, whole putamen, and posterior putamen. The absolute rate of decline in PD was significantly greater than in controls in all subregions, but did not differ significantly by region. Ratios of uptake between regions did not change during the study with the exception of the IL putamen/caudate ratio. Both male gender and advancing age were associated with lower baseline FDOPA uptake in PD, but no difference in decline rates. In the PD group, decline rates were marginally greater during earlier time segments. Striatal FDOPA uptake was significantly correlated with disease duration and with progression of time during the study, but only moderately correlated with UPDRS scores. We conclude that FDOPA uptake in subregions of the striatum is strongly correlated with disease duration and age, and declines equally from symptom onset in PD. This implies that in idiopathic PD, relative preservation of uptake in the anterior striatum reflects a delay in pathologic involvement of nigrostriatal projections to these regions.
PMCID: PMC3080432  PMID: 21449008
Parkinson’s disease; Fluorodopa positron emission tomography; disease progression; aging; gender
6.  A Within-Subject Comparison of 6-[18F]Fluoro-m-tyrosine and 6-[18F]Fluoro-l-dopa in Parkinson’s Disease 
Movement Disorders  2011;26(11):2032-2038.
Progression of Parkinson’s disease symptoms is imperfectly correlated with positron emission tomography biomarkers for dopamine biosynthetic pathways. The radiopharmaceutical 6-[18F]fluoro-m-tyrosine is not a substrate for catechol-O-methyltransferase and therefore has a more favorable uptake-to-background ratio than 6-[18F]fluoro-l-dopa. The objective of this study was to evaluate 6-[18F]fluoro-m-tyrosine relative to 6-[18F]fluoro-l-dopa with partial catechol-O-methyltransferase inhibition as a biomarker for clinical status in Parkinson’s disease. Twelve patients with early-stage Parkinson’s disease, off medication, underwent Unified Parkinson Disease Rating Scale scoring, brain magnetic resonance imaging, and 3-dimensional dynamic positron emission tomography using equivalent doses of 6-[18F]fluoro-m-tyrosine and 6-[18F]fluoro-l-dopa with tolcapone, a catechol-O-methyltransferase inhibitor. Images were realigned within subject, after which the tissue-derived uptake rate constant was generated for volumes of interest encompassing the caudate nucleus, putamen, and subregions of the putamen. We computed both bivariate (Pearson) and partial (covariate of age) correlations between clinical subscores and tissue-derived uptake rate constant. Tissue-derived uptake rate constant values were correlated between the radiopharmaceuticals (r = 0.8). Motor subscores were inversely correlated with the contralateral putamen 6-[18F]fluoro-m-tyrosine tissue-derived uptake rate constant (|r| > 0.72, P < .005) but not significantly with the 6-[18F]fluoro-l-dopa tissue- derived uptake rate constant. The uptake rate constants for both radiopharmaceuticals were also inversely correlated with activities of daily living subscores, but the magnitude of correlation coefficients was greater for 6-[18F]fluoro-m-tyrosine. In this design, 6-[18F]fluoro-m-tyrosine uptake better reflected clinical status than did 6-[18F]fluoro-l-dopa uptake. We attribute this finding to 6-[18F]fluoro-m-tyrosine’s higher affinity for the target, l-aromatic amino acid decarboxylase, and the absence of other major determinants of the uptake rate constant. These results also imply that l-aromatic amino acid decarboxylase activity is a major determinant of clinical status.
PMCID: PMC3278160  PMID: 21638324
positron emission tomography; Parkinson’s disease/radionuclide imaging; dopamine/metabolism
7.  Low HDL Cholesterol is Associated with Lower Gray Matter Volume in Cognitively Healthy Adults 
Dyslipidemia is common in adults and contributes to high rates of cardiovascular disease and may be linked to subsequent neurodegenerative and neurovascular diseases. This study examined whether lower brain volumes and cognition associated with dyslipidemia could be observed in cognitively healthy adults, and whether apolipoprotein E (APOE) genotype or family history of Alzheimer's disease (FHAD) alters this effect. T1-weighted magnetic resonance imaging was used to examine regional brain gray matter (GM) and white matter (WM) in 183 individuals (58.4 ± 8.0 years) using voxel-based morphometry. A non-parametric multiple linear regression model was used to assess the effect of high-density lipoprotein (HDL) and non-HDL cholesterol, APOE, and FHAD on regional GM and WM volume. A post hoc analysis was used to assess whether any significant correlations found within the volumetric analysis had an effect on cognition. HDL was positively correlated with GM volume in the bilateral temporal poles, middle temporal gyri, temporo-occipital gyri, and left superior temporal gyrus and parahippocampal region. This effect was independent of APOE and FHAD. A significant association between HDL and the Brief Visuospatial Memory Test was found. Additionally, GM volume within the right middle temporal gyrus, the region most affected by HDL, was significantly associated with the Controlled Oral Word Association Test and the Center for Epidemiological Studies Depression Scale. These findings suggest that adults with decreased levels of HDL cholesterol may be experiencing cognitive changes and GM reductions in regions associated with neurodegenerative disease and therefore, may be at greater risk for future cognitive decline.
PMCID: PMC2914583  PMID: 20725527
HDL; cholesterol; brain; gray; matter; volume; Alzheimer's; dementia
8.  NSAIDs May Protect Against Age-Related Brain Atrophy 
The use of non-steroidal anti-inflammatory drugs (NSAIDs) in humans is associated with brain differences including decreased number of activated microglia. In animals, NSAIDs are associated with reduced microglia, decreased amyloid burden, and neuronal preservation. Several studies suggest NSAIDs protect brain regions affected in the earliest stages of AD, including hippocampal and parahippocampal regions. In this cross-sectional study, we examined the protective effect of NSAID use on gray matter volume in a group of middle-aged and older NSAID users (n = 25) compared to non-user controls (n = 50). All participants underwent neuropsychological testing and T1-weighted magnetic resonance imaging. Non-user controls showed smaller volume in portions of the left hippocampus compared to NSAID users. Age-related loss of volume differed between groups, with controls showing greater medial temporal lobe volume loss with age compared to NSAID users. These results should be considered preliminary, but support previous reports that NSAIDs may modulate age-related loss of brain volume.
PMCID: PMC2944647  PMID: 20877426
Alzheimer's disease; aging; risk factors; volumetric MRI; NSAIDs

Results 1-8 (8)