Browsing by Author "Yoder, K. K."

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    Cerebral hypometabolism in carriers of the intron 10 +3 MAPT mutation
    (Office of the Vice Chancellor for Research, 2014-04-11) Deters, K. D.; Risacher, Shannon L.; Farlow, Martin R.; Unverzagt, F. W.; Kareken, D. A.; Hutchins, Gary D.; Yoder, K. K.; Murrell, J. R.; Spina, S.; Epperson, Francine; Saykin, Andrew J.; Ghetti, B.
    Introduction: Multiple systems tauopathy with presenile dementia (MSTD), a form of frontotemporal dementia with parkinsonism-17 (FTDP-17), is a neurodegenerative disorder caused by an (a) to (g) transition at position +3 of intron 10 of the microtubule associated protein tau (MAPT) gene. The mutation causes over-expression of 4 repeat (4R) tau isoforms with increased 4R/3R ratio leading to neurodegeneration. Clinically, these patients primarily present with behavior variant FTD (bvFTD), showing disinhibition, and disordered social comportment, as well as impaired executive function, memory, and speech. While altered glucose metabolism has been reported in subjects with sporadic bvFTD, it has yet to be reported in an MSTD sample of this size carrying the intron 10 + 3 mutation. In this study, we used voxel-based analysis to assess brain metabolism using fluorodeoxyglucose (FDG) positron emission tomography (PET) in eleven mutation carriers and eight non-carriers. Methods: Eleven MAPT intron 10 + 3 mutation carriers (5 males; mean age = 48.0 +/- 6.9 years) and eight non-carriers (2 males; mean age = 43.7 +/- 12.0 years) were imaged using FDG PET with standard techniques. Briefly, dynamic PET imaging for 60 minutes followed an intravenous injection of 5-10 mCi of FDG. Scans were then reconstructed using standard techniques, pre-processed for motion correction, and normalized to MNI space. A static FDG image from 30-60 minutes was created from the appropriate frames and normalized to a cerebellar gray matter reference region to create an SUVR image for each participant. These SUVR images were then assessed on a voxel-wise basis for the effect of mutation carrier status, covaried for age at scan and gender and masked using a whole-brain mask. Results were displayed at a voxel-wise threshold of p<0.01 (uncorrected) and minimum cluster size (k) = 50 voxels. SPM8 was used for all pre-processing and voxel-wise statistical analyses. Results: Eight of the MAPT intron 10 + 3 mutation carriers showed mild cognitive impairment at the time of the PET scan (MMSE = 25.3 +/- 2.4), while three MAPT intron 10 + 3 carriers were not impaired at the time of scan (MMSE = 28.0 +/- 0.0). Non-carriers had no cognitive impairment at the time of PET scan (MMSE = 27.1 +/- 1.6). Overall, MAPT mutation carriers showed lower FDG uptake bilaterally in the hippocampus, parahippocampal gyrus, amygdala, superior parietal lobule, and in the prefrontal cortex compared to non-carriers. Conclusions: The present findings suggest individuals with the MAPT mutation at position +3 of intron 10 show symmetrical glucose hypometabolism relative to non-carriers in the medial temporal lobe, parietal cortex, and frontal cortex. These metabolic changes overlap previously described patterns of neurodegeneration in MSTD patients and are consistent with the characteristics of their cognitive dysfunction.
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    Differences in Dopamine Function in Fibromyalgia
    (Office of the Vice Chancellor for Research, 2014-04-11) Albrecht, D. A.; Christian, B. T.; MacKie, P.; Yoder, K. K.
    Objective: Fibromyalgia (FM) is a debilitating pain disorder that affects 2% of the population. Many of the drugs prescribed to fibromyalgia sufferers are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms of fibromyalgia. The neurobiological substrates of fibromyalgia are unknown, but there is evidence for involvement of altered dopaminergic transmission in pain disorders. Given that dopamine is essential for proper cognitive function, it is possible that fibromyalgia symptoms are partly mediated by abnormal dopaminergic functioning. However, the in vivo dopamine system in fibromyalgia patients has not been assessed. Thus, the objective of the current study was to ascertain how the dopamine system in fibromyalgia differs from healthy controls. Methods: [18F]-Fallypride (FAL) PET scanning was used to assess DA changes during a working memory task relative to a baseline task. Twelve patients with FM and twelve controls completed study procedures. Subjects received one FAL PET scan during a 2-back working-memory condition and one during a 0-back (attentional control) task. Results: Fibromyalgia subjects had higher baseline FAL binding potential (BPND) in the right amygdala and ventral pallidum relative to controls. FM subjects had lower baseline FAL BPND in frontal, temporal, and cingulate cortices. Voxel-wise paired t-tests were used to infer increases or decreases in FAL BPND (indicative of decreases or increases in dopamine, respectively) during 2-back performance. Fibromyalgia subjects had significant dopamine release in the ACC, left insula, OFC, and bilateral hippocampus during the 2-back task. Conversely, decreases in DA were detected in the posterior parietal cortex and vmPFC. In controls, dopamine appeared to decrease in the posterior parietal lobe, left hippocampus, and vmPFC during the 2-back task. No significant DA release was detected in controls. Self-reported pain ratings in fibromyalgia subjects were significantly associated with baseline FAL BPND in the ACC, bilateral ventral pallidum, amygdalae, and PAG. Conclusion: These data suggest that in fibromyalgia, abnormalities in dopamine function may be associated with both working memory and pain perception. Further studies are needed to further explore the potential associations between dopamine and cognitive performance and pain perception in FM.
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    Urine THC Metabolite Levels Correlate with Striatal D2/D3 Receptor Availability
    (Office of the Vice Chancellor for Research, 2013-04-05) Albrecht, D. S.; Skosnik, P. D.; Vollmer, J. M.; Brumbaugh, M. S.; Perry, K. M.; Zheng, Q. H.; Federici, L. M.; Patton, E. A.; Herring, C. M.; Yoder, K. K.
    Rationale: Although the incidence of cannabis abuse/dependence in Americans is rising, the neurobiology of cannabis addiction is not well understood. Recent imaging studies have demonstrated deficits in striatal D2/D3 receptor availability in several substance-dependent populations. However, this has not been studied in chronic cannabis users. Objective: The purpose of this study was to compare striatal D2/D3 receptor availability between currently using chronic cannabis users and healthy controls. Methods: Eighteen right-handed males, age 18-35 were studied. Ten subjects were chronic cannabis users; eight were demographically matched controls. Subject eligibility was determined during a screening interview, which included SCID-I and SCID-II assessments, self-report of past substance use, and drug toxicology screening. Subjects underwent a [11C]raclopride (RAC) PET scan; striatal RAC binding potential (BPND) was calculated on a voxel-wise basis with the multilinear reference tissue method. Prior to scanning, urine samples were obtained from cannabis users for quantification of urine Δ-9-tetrahydrocannabinol (THC) and THC metabolites (11-nor-Δ-9-THC-9-carboxylic acid; THC-COOH). Statistical analyses were conducted at voxel-wise level within the striatum. Two-sample t-tests were used to test for differences in BPND between groups. For cannabis subjects, multiple regression analyses were used to test for correlations between striatal BPND and urine THC/THC metabolite levels. Results: There were no differences in BPND between cannabis smokers and healthy controls. Smokers – regardless of substance – had 10% lower D2/D3 availability than non-smokers. Voxel-wise analyses revealed that striatal RAC BPND values were associated with urine levels of cannabis metabolites. Conclusions: Cannabis and cannabis metabolites in urine, markers of recent cannabis consumption, are negatively correlated with striatal RAC BPND. This provides the first evidence that degree of cannabis use is related to changes in the central DA system. Low BPND in both cannabis and cigarette users may indicate a deficiency in D2/D3 receptors as a function of chronic exposure to either or both substances. Alternatively, endogenous dopamine levels may be higher in smokers as a result of MAO inhibition from beta-carbolines in the inhaled smoke. Additional studies are needed to understand the complex relationships between chronic cannabis use and the dopamine system.