Catherine L Gallagher

University of Wisconsin–Madison, Madison, Wisconsin, United States

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Publications (25)144.72 Total impact

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    ABSTRACT: 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.
    Brain Imaging and Behavior 12/2014; DOI:10.1007/s11682-014-9338-4 · 3.39 Impact Factor
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    ABSTRACT: This study tested the hypothesis that frequent participation in cognitively-stimulating activities, specifically those related to playing games and puzzles, is beneficial to brain health and cognition among middle-aged adults at increased risk for Alzheimer's disease (AD). Three hundred twenty-nine cognitively normal, middle-aged adults (age range, 43.2-73.8 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention (WRAP) participated in this study. They reported their current engagement in cognitive activities using a modified version of the Cognitive Activity Scale (CAS), underwent a structural MRI scan, and completed a comprehensive cognitive battery. FreeSurfer was used to derive gray matter (GM) volumes from AD-related regions of interest (ROIs), and composite measures of episodic memory and executive function were obtained from the cognitive tests. Covariate-adjusted least squares analyses were used to examine the association between the Games item on the CAS (CAS-Games) and both GM volumes and cognitive composites. Higher scores on CAS-Games were associated with greater GM volumes in several ROIs including the hippocampus, posterior cingulate, anterior cingulate, and middle frontal gyrus. Similarly, CAS-Games scores were positively associated with scores on the Immediate Memory, Verbal Learning & Memory, and Speed & Flexibility domains. These findings were not modified by known risk factors for AD. In addition, the Total score on the CAS was not as sensitive as CAS-Games to the examined brain and cognitive measures. For some individuals, participation in cognitive activities pertinent to game playing may help prevent AD by preserving brain structures and cognitive functions vulnerable to AD pathophysiology.
    Brain Imaging and Behavior 10/2014; 10(4). DOI:10.1007/s11682-014-9329-5 · 3.39 Impact Factor
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    ABSTRACT: Cardiorespiratory fitness (CRF) is an objective measure of habitual physical activity (PA), and has been linked to increased brain structure and cognition. The gold standard method for measuring CRF is graded exercise testing (GXT), but GXT is not feasible in many settings. The objective of this study was to examine whether a non-exercise estimate of CRF is related to gray matter (GM) volumes, white matter hyperintensities (WMH), cognition, objective and subjective memory function, and mood in a middle-aged cohort at risk for Alzheimer's disease (AD). Three hundred and fifteen cognitively healthy adults (mean age =58.58 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent structural MRI scanning, cognitive testing, anthropometric assessment, venipuncture for laboratory tests, and completed a self-reported PA questionnaire. A subset (n = 85) underwent maximal GXT. CRF was estimated using a previously validated equation incorporating sex, age, body-mass index, resting heart rate, and self-reported PA. Results indicated that the CRF estimate was significantly associated with GXT-derived peak oxygen consumption, validating its use as a non-exercise CRF measure in our sample. Support for this finding was seen in significant associations between the CRF estimate and several cardiovascular risk factors. Higher CRF was associated with greater GM volumes in several AD-relevant brain regions including the hippocampus, amygdala, precuneus, supramarginal gyrus, and rostral middle frontal gyrus. Increased CRF was also associated with lower WMH and better cognitive performance in Verbal Learning & Memory, Speed & Flexibility, and Visuospatial Ability. Lastly, CRF was negatively correlated with self- and informant-reported memory complaints, and depressive symptoms. Together, these findings suggest that habitual participation in physical activity may provide protection for brain structure and cognitive function, thereby decreasing future risk for AD.
    Brain Imaging and Behavior 10/2014; DOI:10.1007/s11682-014-9325-9 · 3.39 Impact Factor
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    ABSTRACT: To examine whether engagement in physical activity might favorably alter the age-dependent evolution of Alzheimer disease (AD)-related brain and cognitive changes in a cohort of at-risk, late-middle-aged adults.
    Neurology 10/2014; DOI:10.1212/WNL.0000000000000964 · 8.30 Impact Factor
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    ABSTRACT: 6-[(18) F]-Fluoro-L-dopa (FDOPA) has been widely used as a biomarker for catecholamine synthesis, storage, and metabolism-its intense uptake in the striatum, and fainter uptake in other brain regions, is correlated with the symptoms and pathophysiology of Parkinson's disease (PD). 6-[(18) F]fluoro-m-tyrosine (FMT), which also targets L-amino acid decarboxylase, has potential advantages over FDOPA as a radiotracer because it does not form catechol-O-methyltransferase (COMT) metabolites. The purpose of the present study was to compare the regional distribution of these radiotracers in the brains of PD patients. 15 Parkinson's patients were studied with FMT and FDOPA positron emission tomography (PET) as well as high-resolution structural magnetic resonance imaging (MRI). MRI's were automatically parcellated into neuroanatomical regions of interest (ROIs) in Freesurfer (http://surfer.nmr.mgh.harvard.edu); region-specific uptake rate constants (Kocc ) were generated from coregistered PET using a Patlak graphical approach. The essential findings were as follows: (1) regional Kocc were highly correlated between the radiotracers and in agreement with a previous FDOPA studies that used different ROI selection techniques; (2) FMT Kocc were higher in extrastriatal regions of relatively large uptake such as amygdala, pallidum, brainstem, hippocampus, entorhinal cortex, and thalamus, whereas cortical Kocc were similar between radiotracers; (3) while subcortical uptake of both radiotracers was related to disease duration and severity, cortical uptake was not. These results suggest that FMT may have advantages for examining pathologic changes within allocortical loop structures, which may contribute to cognitive and emotional symptoms of PD. Synapse, 2014. © 2014 Wiley Periodicals, Inc.
    Synapse 08/2014; 68(8). DOI:10.1002/syn.21745 · 2.43 Impact Factor
  • Alzheimer's and Dementia 07/2014; 10(4):P308. DOI:10.1016/j.jalz.2014.05.246 · 17.47 Impact Factor
  • Alzheimer's and Dementia 07/2014; 10(4):P756. DOI:10.1016/j.jalz.2014.05.1437 · 17.47 Impact Factor
  • Alzheimer's and Dementia 07/2014; 10(4):P66. DOI:10.1016/j.jalz.2014.05.124 · 17.47 Impact Factor
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    ABSTRACT: The relative influence of amyloid burden, neuronal structure and function, and prior cognitive performance on prospective memory decline among asymptomatic late middle-aged individuals at risk for Alzheimer's disease (AD) is currently unknown. We investigated this using longitudinal cognitive data from 122 middle-aged adults (21 "Decliners" and 101 "Stables") enrolled in the Wisconsin Registry for Alzheimer's Prevention who underwent multimodality neuroimaging [11C-Pittsburgh Compound B (PiB), 18F-fluorodeoxyglucose (FDG), and structural/functional magnetic resonance imaging (fMRI)] 5.7 ± 1.4 years (range = 2.9-8.9) after their baseline cognitive assessment. Covariate-adjusted regression analyses revealed that the only imaging measure that significantly distinguished Decliners from Stables (p = .027) was a Neuronal Function composite derived from FDG and fMRI. In contrast, several cognitive measures, especially those that tap episodic memory, significantly distinguished the groups (p's<.05). Complementary receiver operating characteristic curve analyses identified the Brief Visuospatial Memory Test-Revised (BVMT-R) Total (.82 ± .05, p < .001), the BVMT-R Delayed Recall (.73 ± .06, p = .001), and the Reading subtest from the Wide-Range Achievement Test-III (.72 ± .06, p = .002) as the top three measures that best discriminated the groups. These findings suggest that early memory test performance might serve a more clinically pivotal role in forecasting future cognitive course than is currently presumed. (JINS, 2014, 20, 1-12).
    Journal of the International Neuropsychological Society 03/2014; DOI:10.1017/S1355617714000113 · 3.01 Impact Factor
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    ABSTRACT: 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.
    01/2014; 4. DOI:10.1016/j.nicl.2014.02.001
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    ABSTRACT: To determine the relationship between amyloid burden and neural function in healthy adults at risk for Alzheimer's Disease (AD), we used multimodal imaging with [C-11]Pittsburgh compound B positron emission tomography, [F-18]fluorodeoxyglucose, positron emission tomography , and magnetic resonance imaging, together with cognitive measurement in 201 subjects (mean age, 60.1 years; range, 46-73 years) from the Wisconsin Registry for Alzheimer's Prevention. Using a qualitative rating, 18% of the samples were strongly positive Beta-amyloid (Aβ+), 41% indeterminate (Aβi), and 41% negative (Aβ-). Aβ+ was associated with older age, female sex, and showed trends for maternal family history of AD and APOE4. Relative to the Aβ- group, Aβ+ and Aβi participants had increased glucose metabolism in the bilateral thalamus; Aβ+ participants also had increased metabolism in the bilateral superior temporal gyrus. Aβ+ participants exhibited increased gray matter in the lateral parietal lobe bilaterally relative to the Aβ- group, and no areas of significant atrophy. Cognitive performance and self report cognitive and affective symptoms did not differ between groups. Amyloid burden can be identified in adults at a mean age of 60 years and is accompanied by glucometabolic increases in specific areas, but not atrophy or cognitive loss. This asymptomatic stage may be an opportune window for intervention to prevent progression to symptomatic AD.
    Neurobiology of aging 10/2013; 35(3). DOI:10.1016/j.neurobiolaging.2013.09.028 · 4.85 Impact Factor
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    ABSTRACT: Background 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. Conclusions The results underscore the importance of reducing the number of cardiovascular risk factors for maintaining CBF and cognition in an aging population.
    Obesity 07/2013; 21(7). DOI:10.1002/oby.20170 · 4.39 Impact Factor
  • Journal of the International Neuropsychological Society 04/2013; 19(4):492. DOI:10.1017/S1355617713000404 · 3.01 Impact Factor
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    ABSTRACT: Recent studies suggest that white matter abnormalities contribute to both motor and non-motor symptoms of Parkinson's disease. The present study was designed to investigate the degree to which diffusion tensor magnetic resonance imaging (DTI) indices are related to executive function in Parkinson's patients. We used tract-based spatial statistics to compare DTI data from 15 patients to 15 healthy, age- and education-matched controls. We then extracted mean values of fractional anisotropy (FA) and mean diffusivity (MD) within an a priori frontal mask. Executive function composite Z scores were regressed against these DTI indices, age, and total intracranial volume. In Parkinson's patients, FA was related to executive composite scores, and both indices were related to Stroop interference scores. We conclude that white matter microstructural abnormalities contribute to cognitive deficits in Parkinson's disease. Further work is needed to determine whether these white matter changes reflect the pathological process or a clinically important comorbidity. (JINS, 2013, 19, 1-6).
    Journal of the International Neuropsychological Society 01/2013; 19(3):1-6. DOI:10.1017/S1355617712001373 · 3.01 Impact Factor
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    ABSTRACT: Cerebral blood flow (CBF) provides an indication of the metabolic status of the cortex and may have utility in elucidating preclinical brain changes in persons at risk for Alzheimer's disease (AD) and related diseases. In this study, we investigated CBF in 327 well-characterized adults including patients with AD (n = 28), patients with amnestic mild cognitive impairment (aMCI, n = 23), older cognitively normal (OCN, n = 24) adults, and asymptomatic middle-aged adults (n = 252) with and without a family history (FH) of AD. Compared with the asymptomatic cohort, AD patients displayed significant hypoperfusion in the precuneus, posterior cingulate, lateral parietal cortex, and the hippocampal region. Patients with aMCI exhibited a similar but less marked pattern of hypoperfusion. Perfusion deficits within the OCN adults were primarily localized to the inferior parietal lobules. Asymptomatic participants with a maternal FH of AD showed hypoperfusion in hippocampal and parietofrontal regions compared with those without a FH of AD or those with only a paternal FH of AD. These observations persisted when gray matter volume was included as a voxel-wise covariate. Our findings suggest that having a mother with AD might confer a particular risk for AD-related cerebral hypoperfusion in midlife. In addition, they provide further support for the potential utility of arterial spin labeling for the measurement of AD-related neurometabolic dysfunction, particularly in situations where [18F]fluorodeoxyglucose imaging is infeasible or clinically contraindicated.
    Cerebral Cortex 12/2012; DOI:10.1093/cercor/bhs381 · 8.31 Impact Factor
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    ABSTRACT: 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.
    American Journal of Nuclear Medicine and Molecular Imaging 01/2012; 2(4):475-82. · 3.25 Impact Factor
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    ABSTRACT: Progression of Parkinson's disease symptoms is imperfectly correlated with positron emission tomography biomarkers for dopamine biosynthetic pathways. The radiopharmaceutical 6-[(18) F]fluoro-m-tyrosine is not a substrate for catechol-O-methyltransferase and therefore has a more favorable uptake-to-background ratio than 6-[(18) F]fluoro-L-dopa. The objective of this study was to evaluate 6-[(18) F]fluoro-m-tyrosine relative to 6-[(18) F]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-[(18) F]fluoro-m-tyrosine and 6-[(18) F]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-[(18) F]fluoro-m-tyrosine tissue-derived uptake rate constant (|r| > 0.72, P < .005) but not significantly with the 6-[(18) F]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-[(18) F]fluoro-m-tyrosine. In this design, 6-[(18) F]fluoro-m-tyrosine uptake better reflected clinical status than did 6-[(18) F]fluoro-L-dopa uptake. We attribute this finding to 6-[(18) F]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.
    Movement Disorders 09/2011; 26(11):2032-8. DOI:10.1002/mds.23778 · 5.63 Impact Factor
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    ABSTRACT: Although [(18)F]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.
    Brain Imaging and Behavior 05/2011; 5(3):203-11. DOI:10.1007/s11682-011-9124-5 · 3.39 Impact Factor
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    ABSTRACT: Rate of decline in 6-L-[(18)F]fluorodopa (FDOPA) uptake within the striatum has been reported as showing regional differences in Parkinson's disease (PD). We acquired longitudinal brain FDOPA positron emission tomography (PET) studies in 26 PD subjects and 11 controls over 4.5 years. We analyzed both spatially normalized voxel-wise maps of radiotracer influx (Kocc) and average Kocc values for six non-overlapping volumes of interest (VOIs) encompassing the striatum. The voxel-wise analysis showed that in PD, FDOPA Kocc decline spanned the striatum but was greatest in the posterior putamen ipsilateral and anterior putamen contralateral to initial symptoms. The VOI approached showed that absolute rates of Kocc decline were significantly greater in PD than control subjects, but that the slope of decline did not differ between subregions. In PD, ratios of uptake between subregions did not change during the study with the exception of the ipsilateral putamen/caudate ratio. Decline rates were marginally greater during earlier time segments. Both male gender and advancing age were associated with lower baseline FDOPA uptake, but no difference in decline rates. VOI Kocc values were significantly correlated with disease duration, but only moderately correlated with clinical measures. We conclude that FDOPA uptake in subregions of the striatum is strongly correlated with disease duration and age, and declines approximately 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 this region.
    Movement Disorders 03/2011; 26(4):614-20. DOI:10.1002/mds.23503 · 5.63 Impact Factor
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    ABSTRACT: 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.
    Frontiers in Aging Neuroscience 09/2010; 2. DOI:10.3389/fnagi.2010.00035 · 2.84 Impact Factor