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1.
Neurobiol Aging ; 92: 73-74, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32402985

RESUMO

Elevated low-density lipoprotein cholesterol and total cholesterol in midlife and decline in total cholesterol from mid- to late-life are associated with incident dementia. Whether brain amyloid deposition mediates this relationship is unclear. We explored the association between midlife blood lipid levels and mid- to late-life change in lipid levels with brain amyloid deposition assessed using florbetapir PET scans in a biracial sample of 325 nondemented participants of the Atherosclerosis Risk in Communities-PET Amyloid Imaging study. Midlife total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were not significantly associated with late-life amyloid burden after adjusting for covariates. Associations between changes in lipids and late-life amyloid deposition were similarly null. Lipids may contribute to dementia risk through alternate mechanisms.

2.
Anesthesiology ; 132(6): 1407-1418, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32412719

RESUMO

BACKGROUND: As more older adults undergo surgery, it is critical to understand the long-term effects of surgery on brain health, particularly in relation to the development of Alzheimer's disease. This study examined the association of surgical hospitalization with subsequent brain ß-amyloid deposition in nondemented older adults. METHODS: The Atherosclerosis Risk in Communities-Positron Emission Tomography (ARIC-PET) study is a prospective cohort study of 346 participants without dementia who underwent florbetapir PET imaging. Active surveillance of local hospitals and annual participant contact were used to gather hospitalization and surgical information (International Classification of Disease, Ninth Revision, Clinical Modification codes) over the preceding 24-yr period. Brain amyloid measured using florbetapir PET imaging was the primary outcome. Elevated amyloid was defined as a standardized uptake value ratio of more than 1.2. RESULTS: Of the 313 participants included in this analysis (age at PET: 76.0 [SD 5.4]; 56% female), 72% had a prior hospitalization, and 50% had a prior surgical hospitalization. Elevated amyloid occurred in 87 of 156 (56%) participants with previous surgical hospitalization, compared with 45 of 87 (52%) participants who had no previous hospitalization. Participants with previous surgical hospitalizations did not show an increased odds of elevated brain amyloid (odds ratio, 1.32; 95% CI, 0.72 to 2.40; P = 0.370) after adjusting for confounders (primary analysis). Results were similar using the reference group of all participants without previous surgery (hospitalized and nonhospitalized; odds ratio, 1.58; 95% CI, 0.96 to 2.58; P = 0.070). In a prespecified secondary analysis, participants with previous surgical hospitalization did demonstrate increased odds of elevated amyloid when compared with participants hospitalized without surgery (odds ratio, 2.10; 95% CI, 1.09 to 4.05; P = 0.026). However, these results were attenuated and nonsignificant when alternative thresholds for amyloid-positive status were used. CONCLUSIONS: The results do not support an association between surgical hospitalization and elevated brain amyloid.

3.
J Neurovirol ; 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32270469

RESUMO

The causes of cognitive impairment among older HIV+ individuals may overlap with causes among elderly HIV seronegative (HIV-) individuals. The objective of this study was to determine if beta-amyloid (Aß) deposition measured by [18F] AV-45 (florbetapir) positron emission tomography (PET) is increased in older HIV+ individuals compared to HIV- individuals. Forty-eight HIV+ and 25 HIV- individuals underwent [18F] AV-45 PET imaging. [18F] AV-45 binding to Aß was measured by standardized uptake value ratios (SUVR) relative to the cerebellum in 16 cortical and subcortical regions of interest. Global and regional cortical SUVRs were compared by (1) serostatus, (2) HAND stage, and (3) age decade, comparing individuals in their 50s and > 60s. There were no differences in median global cortical SUVR stratified by HIV serostatus or HAND stage. The proportion of HIV+ participants in their 50s with elevated global amyloid uptake (SUVR > 1.40) was significantly higher than the proportion in HIV- participants (67% versus 25%, p = 0.04), and selected regional SUVR values were also higher (p < 0.05) in HIV+ compared to HIV- participants in their 50s. However, these group differences were not seen in participants in their 60s. In conclusion, PET imaging found no differences in overall global Aß deposition stratified by HIV serostatus or HAND stage. Although there was some evidence of increased Aß deposition in HIV+ individuals in their 50s compared to HIV- individuals which might indicate premature aging, the most parsimonious explanation for this is the relatively small sample size in this cross-sectional cohort study.

4.
J Neural Eng ; 17(2): 025001, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32084654

RESUMO

OBJECTIVE: We report the transcranial functional photoacoustic (fPA) neuroimaging of N-methyl-D-aspartate (NMDA) evoked neural activity in the rat hippocampus. Concurrent quantitative electroencephalography (qEEG) and microdialysis were used to record real-time circuit dynamics and excitatory neurotransmitter concentrations, respectively. APPROACH: We hypothesized that location-specific fPA voltage-sensitive dye (VSD) contrast would identify neural activity changes in the hippocampus which correlate with NMDA-evoked excitatory neurotransmission. MAIN RESULTS: Transcranial fPA VSD imaging at the contralateral side of the microdialysis probe provided NMDA-evoked VSD responses with positive correlation to extracellular glutamate concentration changes. qEEG validated a wide range of glutamatergic excitation, which culminated in focal seizure activity after a high NMDA dose. We conclude that transcranial fPA VSD imaging can distinguish focal glutamate loads in the rat hippocampus, based on the VSD redistribution mechanism which is sensitive to the electrophysiologic membrane potential. SIGNIFICANCE: Our results suggest the future utility of this emerging technology in both laboratory and clinical sciences as an innovative functional neuroimaging modality.

6.
J Cereb Blood Flow Metab ; 40(2): 288-297, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30755135

RESUMO

Surrogates of neuronal activity, typically measured by regional cerebral blood flow (rCBF) or glucose metabolism, can be estimated from dynamic amyloid PET imaging. Using data for 149 participants (345 visits) from the Baltimore Longitudinal Study of Aging, we assessed whether the average of early amyloid frames (EA) and R1 computed from dynamic 11C-Pittsburgh compound B (PiB) PET can serve as surrogates of rCBF computed from 15O-H2O-PET. R1 had the highest longitudinal test-retest reliability. Interquartile range (IQR) of cross-sectional Pearson correlations with rCBF was 0.60-0.72 for EA and 0.63-0.72 for R1. Correlations between rates of change were lower (IQR 0.22-0.50 for EA, 0.25-0.55 for R1). Values in the Alzheimer's metabolic signature meta-ROI were negatively associated with age and exhibited longitudinal declines for each PET measure. In age-adjusted analyses, meta-ROI rCBF and R1 were lower among amyloid+ individuals; EA and R1 were lower among males. Regional PiB-based measures, in particular R1, can be suitable surrogates of rCBF. Dynamic PiB-PET may obviate the need for a separate scan to measure neuronal activity, thereby reducing patient burden, radioactivity exposure, and cost.

7.
Pain ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31764386

RESUMO

Although ethnic differences in pain perception are well documented, the underlying mechanism for these outcomes has not been established. µ-opioid receptor (MOR) function might contribute to this disparity, given that MORs play a key role in pain sensitivity and modulation. However, no study has characterized ethnic differences in MOR physiology. The present study sought to address this knowledge gap by examining differences in µ-selective agonist binding potential (BPND; [C]-Carfentanil) between 27 non-Hispanic Black (NHB) and 27 demographically-similar, non-Hispanic White (NHW) participants. Participants completed questionnaires and two 90-minute high-resolution research tomograph PET imaging sessions. During PET imaging, a capsaicin or control cream was applied to individuals' arms and pain ratings were collected. Bonferroni-corrected PET volumes of interest analyses revealed significantly greater [C]-Carfentanil BPND among NHB participants in bilateral ventral striata [(left): F1,52=16.38, p<.001; (right): F1,52=21.76, p<.001], bilateral dorsolateral prefrontal cortices [(left) F1,52=17.3, p<.001; (right): F1,52=14.17, p<.001], bilateral subgenual anterior cingulate cortex [(left): F1,52=10.4, p=.002; (right): F1,52=12.91, p=.001], and right insula (F1,52=11.0, p=.002). However, there were no significant main effects of Condition or Ethnicity x Condition interaction effects across models, likely attributable to individual variability in the direction of change within groups. BPND values were significantly correlated with pain ratings collected during the capsaicin condition (r range = .34-.46, p range =.01-.001). Results suggest that NHB individuals might have generally greater unoccupied MOR density than NHW peers. Findings have implications for physiological differences underlying ethnicity-related pain disparities. If replicated, these results further emphasize the need for tailored treatments in historically underserved populations.

8.
Stroke ; 50(12): 3622-3624, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31597548

RESUMO

Background and Purpose- Cardiovascular disease is a known risk factor for cognitive decline, although the mechanisms remain unclear. We hypothesize that Aß (ß-amyloid), a core pathology of Alzheimer's disease, will be associated with subclinical cardiac structure and function echocardiogram indices. Methods- Three hundred six nondemented participants from the ARIC study (Atherosclerosis Risk in Communities Study) underwent florbetapir positron emission tomography and 2D echocardiography (echo). Cross-sectional associations between echo markers of left ventricular structure and function and global cortical Aß (≥1.2 standardized uptake value ratio were evaluated using multivariable logistic regression with interaction terms when appropriate. Results- Participants ranged in age from 67 to 88 years, were 57% female and 42% black. Per 1 cm increase in end-diastolic left ventricular diameter, the odds of elevated florbetapir standardized uptake value ratio doubled (odds ratio, 2.04 [95% CI, 1.10-3.77]), with similar findings when excluding mild cognitive impairment (odds ratio, 2.61 [95% CI, 1.22-5.59]). Conclusions- We have demonstrated a significant association between a marker of left ventricular structure and elevated florbetapir standardized uptake value ratio, identified using positron emission tomography. Ongoing prospective work will help determine if changes in cardiac structure and function either precede, or occur simultaneously with deposition of amyloid.

9.
Alzheimers Dement (Amst) ; 11: 637-645, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31517026

RESUMO

Introduction: Tau pathology, a hallmark of Alzheimer's disease, is observed in the brains of virtually all individuals over 70 years. Methods: Using 18F-AV-1451 (18F-flortaucipir) positron emission tomography, we evaluated tau pathology in 54 cognitively normal participants (mean age: 77.5 years, SD: 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between positron emission tomography signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status. Results: Greater age, male sex, black race, and amyloid positivity were associated with higher 18F-AV-1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume (ß = -1.124, SE = 0.485, P = .025) and a steeper decline in memory performance (ß = -0.086, SE = 0.039, P = .029). Discussion: Assessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimer's disease.

10.
J Nucl Med ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420499

RESUMO

Emerging evidence supports a hypothesized role of the α7-nicotinic acetylcholine receptor (α7-nAChR) in the pathophysiology of Alzheimer's disease (AD). 18F-ASEM is a radioligand for estimating availability of the α7-nAChR in the brain in vivo with positron emission tomography (PET). Methods: In this cross-sectional study, 14 patients with mild cognitive impairment (MCI), a prodromal stage to dementia, and 17 cognitively intact, elderly controls completed 18F-ASEM PET. For each participant, binding in each region of interest was estimated using Logan graphical analysis with a metabolite-corrected arterial input function. Results: Higher 18F-ASEM binding was observed in MCI compared to controls across all regions, supporting higher availability of the α7-nAChR in MCI. 18F-ASEM binding was not associated with verbal memory in this small MCI sample. Conclusion: These data support use of 18F-ASEM PET to examine further the relationship between α7-nAChR availability and MCI.

11.
Front Neurosci ; 13: 579, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447622

RESUMO

Minimally-invasive monitoring of electrophysiological neural activities in real-time-that enables quantification of neural functions without a need for invasive craniotomy and the longer time constants of fMRI and PET-presents a very challenging yet significant task for neuroimaging. In this paper, we present in vivo functional PA (fPA) imaging of chemoconvulsant rat seizure model with intact scalp using a fluorescence quenching-based cyanine voltage-sensitive dye (VSD) characterized by a lipid vesicle model mimicking different levels of membrane potential variation. The framework also involves use of a near-infrared VSD delivered through the blood-brain barrier (BBB), opened by pharmacological modulation of adenosine receptor signaling. Our normalized time-frequency analysis presented in vivo VSD response in the seizure group significantly distinguishable from those of the control groups at sub-mm spatial resolution. Electroencephalogram (EEG) recording confirmed the changes of severity and frequency of brain activities, induced by chemoconvulsant seizures of the rat brain. The findings demonstrate that the near-infrared fPA VSD imaging is a promising tool for in vivo recording of brain activities through intact scalp, which would pave a way to its future translation in real time human brain imaging.

12.
Parkinsonism Relat Disord ; 64: 235-241, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31053531

RESUMO

INTRODUCTION: Deep brain stimulation (DBS) is an established treatment for Parkinson's Disease (PD). Despite the improvement of motor symptoms in most patients by sub-thalamic nucleus (STN) DBS and its widespread use, the neurobiological mechanisms are not completely understood. The objective of the present study was to elucidate the effects of subthalamic nucleus (STN) DBS in PD on the dopamine system and neural circuitry, employing high-resolution positron emission tomography (PET) imaging. The hypotheses tested were that STN DBS would decrease the striatal vesicular monoamine transporter (VMAT2), secondary to an increase in dopamine concentrations, and would decrease striatal cerebral metabolism and increase cortical cerebral metabolism. METHODS: PET imaging of the vesicular monoamine transporter (VMAT2) and cerebral glucose metabolism was performed prior to DBS surgery and after 4-6 months of STN stimulation in seven PD patients (mean age 67 ±â€¯7). RESULTS: The patients demonstrated significant improvement in motor and neuropsychiatric symptoms after STN DBS. Decreased VMAT2 was observed in the caudate, putamen and associative striatum and in extra-striatal, cortical and limbic regions. Cerebral glucose metabolism was decreased in striatal sub-regions and increased in temporal and parietal cortices and the cerebellum. Decreased striatal VMAT2 was correlated with decreased striatal and increased cortical and limbic metabolism. Improvement of depressive symptoms was correlated with decreased VMAT2 in striatal and extra-striatal regions and with striatal decreases and cortical increases in metabolism. CONCLUSIONS: The present results support further investigation of the role of VMAT2, and associated changes in neural circuitry in the improvement of motor and non-motor symptoms with STN DBS in PD.

13.
J Neurotrauma ; 36(17): 2549-2557, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30963804

RESUMO

Our objective was to examine associations of head injury with total and regional brain amyloid deposition. We performed cross-sectional analyses of 329 non-demented participants (81 with prior head injury) in the Atherosclerosis Risk in Communities-Positron Emission Tomography (ARIC-PET) Study who underwent 18-florbetapir PET imaging in 2012-2014. A history of head injury was defined by self-report or emergency department/hospitalization International Classification of Diseases, Ninth Revision codes. Generalized linear regression models adjusted for demographic, socioeconomic, and dementia/cardiovascular risk factors were used to estimate prevalence ratios (PRs; 95% confidence intervals [CIs]) for elevated (> 1.2) global and regional standard uptake value ratios (SUVRs). Mean age of participants was 76 years, 57% were women, and 43% were black. Head injury was associated with increased prevalence of elevated SUVR >1.2 globally (PR: 1.31; 95% CI: 1.19-1.57), as well as in the orbitofrontal cortex (PR: 1.23); (95% CI: 1.04-1.46), prefrontal cortex (PR: 1.18; 95% CI: 1.00-1.39), superior frontal cortex (PR: 1.24; 95% CI: 1.05-1.48), and posterior cingulate (PR: 1.26; 95% CI: 1.04-1.52). There also was evidence for a dose-response relationship, whereby a history of ≥1 head injury was associated with elevated SUVR >1.2 in the prefrontal cortex and superior frontal cortex compared with persons with a history of one head injury (all, p < 0.05). In conclusion, head injury was associated with increased amyloid deposition globally and in the frontal cortex and posterior cingulate, with suggestion of a dose-response association of head injuries with beta-amyloid deposition. Further work is needed to determine if increased amyloid deposition contributes to dementia in this population.

14.
Neuroimage Clin ; 22: 101795, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30991617

RESUMO

While the ApoE ε4 allele is a known risk factor for mild cognitive impairment (MCI) and Alzheimer's disease, brain region specific effects remain elusive. In this study, we investigate whether the ApoE ε4 allele exhibits brain region specific effects in longitudinal glucose uptake among patients with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed FDG PET images, MRIs, and demographic information were downloaded from the ADNI database. An iterative reblurred Van Cittertiteration method was used for partial volume correction (PVC) on all PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. Longitudinal changes in ROI FDG standardized uptake value ratio (SUVR) relative to cerebellum in 24 ApoE ε4 carriers and 24 age-matched ApoE ε4 non-carriers were measured for up to 84-months (median 72 months, SD = 11.2 months) and compared using a generalized linear mixed effects model controlling for gender, education, baseline age, and follow-up period. Additionally, voxelwise analysis was performed by implementing a paired t-test comparing matched baseline and 72 month FDG SUVR images in ApoE carriers and non-carriers separately. Results with PVC were compared with ones from non-PVC based analysis. After applying PVC, the superior fontal, parietal, lateral temporal, medial temporal, caudate, thalamus, and post-cingulate, and amygdala regions had greater longitudinal decreases in FDG uptake in ApoE ε4 carriers with MCI compared to non-carriers with MCI. Similar forebrain and limbic clusters were found through voxelwise analysis. Compared to the PVC based analysis, fewer significant ApoE-associated regions and clusters were found in the non-PVC based PET analysis. Our findings suggest that the ApoE ε4 genotype is associated with a longitudinal decline in glucose uptake in 8 forebrain and limbic brain regions in the context of MCI. In conclusion, this 84-months longitudinal FDG PET study demonstrates a novel ApoE ε4-associated brain-region specific glucose metabolism pattern in patients with MCI. Partial volume correction improved FDG PET quantification.


Assuntos
Apolipoproteína E4/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Glucose/metabolismo , Neuroimagem/métodos , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons
15.
PLoS One ; 14(3): e0212573, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30893304

RESUMO

BACKGROUND: Pulmonary hypertension (PH) is a known complication of HCM and is a strong predictor of mortality. We aim to investigate the relationship between microvascular dysfunction measured by quantitative PET and PH in HCM patients. METHODS: Eighty-nine symptomatic HCM patients were included in the study. Each patient underwent two 20-min 13N-NH3 dynamic PET scans for rest and stress conditions, respectively. A 2-tissue irreversible compartmental model was used to fit the segments time activity curves for estimating segmental and global myocardial blood flow (MBF) and myocardial flow reserve (MFR). Echocardiographic derived PASP was utilized to estimate PH. RESULTS: Patients were categorized into two groups across PASP: PH (PASP > 36 mmHg) and no-PH (PASP ≤ 36 mmHg). patients with PH had larger left atrium, ratio of higher inflow early diastole (E) and atrial contraction (A) waves, E/A, and ratio of inflow and peak early diastolic waves, E/e', significantly reduced global stress MBF (1.85 ± 0.52 vs. 2.13 ± 0.56 ml/min/g; p = 0.024) and MFR (2.21 ± 0.57 vs. 2.62 ± 0.75; p = 0.005), while the MBFs at rest between the two groups were similar. There were significant negative correlations between global stress MBF/MFR and PASP (stress MBF: r = -0.23, p = 0.03; MFR: r = -0.32, p = 0.002); for regional MBF and MFR measurements, the highest linear correlation coefficients were observed in the septal wall (stress MBF: r = -0.27, p = 0.01; MFR: r = -0.31, p = 0.003). Global MFR was identified to be independent predictor for PH in multivariate regression analysis. CONCLUSION: Echocardiography-derived PASP is negatively correlated with global MFR measured by 13N-NH3 dynamic PET. Global MFR is suggested to be an index of PH in HCM patients.


Assuntos
Pressão Sanguínea , Cardiomiopatia Hipertrófica , Ecocardiografia , Reserva Fracionada de Fluxo Miocárdico , Tomografia por Emissão de Pósitrons , Artéria Pulmonar , Idoso , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia
16.
Neuroimage Clin ; 22: 101769, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30927602

RESUMO

OBJECTIVE: Amyloid positivity is a biomarker of AD pathology, yet the associations between amyloid positivity and brain volumetric changes, especially in the hippocampus, are inconsistent. We hypothesize that sex differences in associations may contribute to inconsistent findings among cognitively normal older adults. METHODS: Using linear mixed effects models, we examined the association of amyloid positivity with prospective volumetric changes (mean = 3.3 visits) of parahippocampal gyrus (phg), hippocampus, entorhinal cortex (erc), precuneus, and fusiform gyrus among 171 Baltimore Longitudinal Study of Aging participants aged ≥55 years. Amyloid positivity was defined by a mean 11C-Pittsburgh Compound B (PiB) distribution volume ratio (DVR) cut-off of 1.062. All analyses included age, race, sex, education, APOE e4 carrier status, and two-way interactions of these covariates with time. Two-way interaction between sex and PiB+/- status and three-way interaction of sex and PiB+/- status with time were added to assess whether sex modified associations. RESULTS: PiB+ status was associated with greater volumetric declines in the phg (ß = -0.036, SE = 0.011, p = 0.001) and erc (ß = -0.019, SE = 0.009, p = 0.045). Sex modified the association of PiB+ status and rates of volumetric declines in fusiform (ß = -0.117, SE = 0.049, p = 0.019). PiB+ males had steeper rates of volumetric declines in phg (ß = -0.051, SE = 0.013, p < 0.001) and erc (ß = -0.029, SE = 0.012, p = 0.014) than PiB- males, while there was no difference in rates of volumetric change between PiB+ and PiB- females. CONCLUSIONS: Amyloidosis is a marker of entorhinal and parahippocampal volume loss. Amyloid positivity is a predictor of volume loss in brain regions affected by early AD pathology in men, but not women.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Caracteres Sexuais , Tiazóis
17.
J Alzheimers Dis ; 68(2): 517-521, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30775981

RESUMO

We examined associations between cognitive reserve and late-life amyloid-ß deposition using florbetapir positron emission tomography (PET). We used data from the Atherosclerosis Risk in Communities (ARIC) and ARIC-PET Study. 330 dementia-free participants underwent PET scans. Mean global cortical standardized uptake value ratio (SUVR) >1.2 was defined as elevated. Midlife cognition was significantly associated with late-life cognition, but not with late-life elevated SUVR; education was not associated with late-life SUVR, but was strongly associated with late-life cognition. Cognitive reserve may reduce dementia risk by mitigating the impact of Alzheimer's disease pathology on the clinical expression of dementia, rather than by altering its pathogenesis.

18.
J Neurochem ; 150(2): 188-201, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30720866

RESUMO

Humans and non-human primates exposed to excess levels of manganese (Mn) exhibit deficits in working memory and attention. Frontal cortex and fronto-striatal networks are implicated in working memory and these circuits rely on dopamine for optimal performance. Here, we aimed to determine if chronic Mn exposure alters in vivo dopamine release (DAR) in the frontal cortex of non-human primates. We used [11 C]-FLB457 positron emission tomography with amphetamine challenge to measure DAR in Cynomolgus macaques. Animals received [11 C]-FLB457 positron emission tomography scans with and without amphetamine challenge prior to Mn exposure (baseline), at different time points during the Mn exposure period, and after 10 months of Mn exposure cessation. Four of six Mn-exposed animals expressed significant impairment of frontal cortex in vivo DAR relative to baseline. One Mn animal had no change in DAR and another Mn animal expressed increased DAR relative to baseline. In the reversal studies, one Mn-exposed animal exhibited complete recovery of DAR while the second animal had partial recovery. In both animals, frontal cortex Mn concentrations normalized after 10 months of exposure cessation based on T1-weighted magnetic resonance imaging. D1-dopamine receptor (D1R) autoradiography in frontal cortex tissue indicates that Mn animals that experienced cessation of Mn exposure expressed D1R levels that were approximately 50% lower than Mn animals that did not experience cessation of Mn exposure or control animals. The present study provides evidence of Mn-induced alterations in frontal cortex DAR and D1R that may be associated with working memory and attention deficits observed in Mn-exposed subjects.

19.
Neuropsychopharmacology ; 44(3): 598-605, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30449883

RESUMO

Dopamine D2 receptor occupancy (D2RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D2RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the present study was to determine D2RO at plasma steady state of 60 mg ITI-007, a dose that previously demonstrated antipsychotic efficacy in a controlled trial, administered orally open-label once daily in the morning for two weeks in patients with schizophrenia (N = 10) and after at least a two-week washout period from standard of care antipsychotics. D2RO was determined using positron emission tomography with 11C-raclopride as the radiotracer. Mean peak dorsal striatal D2RO was 39% at 60 mg ITI-007 occurring 1 h post-dose. Lumateperone was well-tolerated with a favorable safety profile in this study. There were no clinically significant changes in vital signs, ECGs, or clinical chemistry laboratory values, including prolactin levels. There were no adverse event reports of akathisia or other extrapyramidal motor side effects; mean scores on motor function scales indicated no motor disturbances with lumateperone treatment. This level of occupancy is lower than most other antipsychotic drugs at their efficacious doses and likely contributes to the favorable safety and tolerability profile of lumateperone with reduced risk for movement disorders and hyperprolactinemia. If approved, lumateperone may provide a new and safe treatment option for individuals living with schizophrenia.


Assuntos
Antipsicóticos/farmacocinética , Butirofenonas/farmacocinética , Neostriado/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Adulto , Radioisótopos de Carbono , Antagonistas dos Receptores de Dopamina D2/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Racloprida/farmacocinética , Esquizofrenia/diagnóstico por imagem
20.
CNS Neurosci Ther ; 25(1): 136-146, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29923314

RESUMO

AIMS: RPR 102681, a cholecystokinin-B antagonist, increased dopamine (DA) release and reduced cocaine self-administration in animals. This pilot study sought to assess the safety and pharmacokinetics (PK) of co-administration of RPR 102681 and cocaine, and to confirm the DA release mechanism of RPR 102681. METHODS: Sixteen cocaine-dependent participants were randomized to either placebo or RPR102681 at 3 ascending doses; cocaine was co-administered at steady state of RPR 102681. [11 C]raclopride positron emission tomography scans were conducted at baseline and at each RPR102681 dose. RESULTS: RPR 102681 was well tolerated, and safe to co-administer with cocaine. RPR 102681 did not alter the PK of either cocaine or its metabolite benzoylecgonine and showed no intrinsic abuse liability. There was a trend toward reduction of cocaine craving scores. In contrast to animal studies, RPR 102681 significantly increased the binding potential of [11 C]raclopride in the ventral striatum (t test, P < .001) and caudate nucleus (t test, P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA. CONCLUSION: Overall, this pilot study suggests that RPR 102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving.

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