Publications by authors named "Dean F Wong"

199 Publications

Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Idiopathic Autism Spectrum Disorder and Fragile X Syndrome: A Pilot Study.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Multiple lines of evidence suggest that dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR) plays a role in the pathogenesis of autism spectrum disorder (ASD). Yet animal and human investigations of mGluR expression provide conflicting findings about the nature of dysregulation of cerebral mGluR pathways in subtypes of ASD. The demonstration of reduced mGluR expression throughout the living brains of men with fragile X syndrome (FXS), the most common known single-gene cause of ASD, provides a clue to examine mGluR expression in ASD. We aimed to (A) compare and contrast mGluR expression in idiopathic autism spectrum disorder (IASD), FXS, and typical development (TD) and (B) show the value of positron emission tomography (PET) for the application of precision medicine for the diagnosis and treatment of individuals with IASD, FXS, and related conditions. Two teams of investigators independently administered 3-[F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([F]FPEB), a novel, specific mGluR PET ligand to quantitatively measure the density and the distribution of mGluRs in the brain regions, to participants of both sexes with IASD and TD and men with FXS. In contrast to participants with TD, mGluR expression was significantly increased in the cortical regions of participants with IASD and significantly reduced in all regions of men with FXS. These results suggest the feasibility of this protocol as a valuable tool to measure mGluR expression in clinical trials of individuals with IASD and FXS and related conditions.
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http://dx.doi.org/10.3390/ijms22062863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999711PMC
March 2021

Generalizability of findings from a clinical sample to a community-based sample: A comparison of ADNI and ARIC.

Alzheimers Dement 2021 Feb 1. Epub 2021 Feb 1.

Department of Epidemiology, George Washington University, Washington, District of Columbia, USA.

Introduction: Clinic-based study samples, including the Alzheimer's Disease Neuroimaging Initiative (ADNI), offer rich data, but findings may not generalize to community-based settings. We compared associations in ADNI to those in the Atherosclerosis Risk in Communities (ARIC) study to assess generalizability across the two settings.

Methods: We estimated cohort-specific associations among risk factors, cognitive test scores, and neuroimaging outcomes to identify and quantify the extent of significant and substantively meaningful differences in associations between cohorts. We explored whether using more homogenous samples improved comparability in effect estimates.

Results: The proportion of associations that differed significantly between cohorts ranged from 27% to 34% across sample subsets. Many differences were substantively meaningful (e.g., odds ratios [OR] for apolipoprotein E ε4 on amyloid positivity in ARIC: OR = 2.8, in ADNI: OR = 8.6).

Discussion: A higher proportion of associations differed significantly and substantively than would be expected by chance. Findings in clinical samples should be confirmed in more representative samples.
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http://dx.doi.org/10.1002/alz.12293DOI Listing
February 2021

Imaging-based indices of Neuropathology and gait speed decline in older adults: the atherosclerosis risk in communities study.

Brain Imaging Behav 2021 Jan 13. Epub 2021 Jan 13.

Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.

Imaging markers of cerebrovascular disease and Alzheimer's disease (AD) are implicated in mobility impairment in older adults, but few studies have examined these relationships longitudinally in a racially-diverse population-based sample. At Visit 5 (2011-13) of the ARIC Study, 1859 participants had usual pace gait speed (cm/s) assessed and brain MRI (mean age = 76.3, 28.5% Black) and PET (n = 343; mean age = 75.9, 42.6% Black) measures including total/regional brain volume (cm), white matter hyperintensities (WMH; cm), infarcts (present/absent), microbleeds (count) and global beta-amyloid (Aβ). Participants returned at Visit 6 (n = 1264, 2016-17) and Visit 7 (n = 1108, 2018-19) for follow-up gait speed assessments. We used linear regression to estimate effects of baseline infarct presence, higher microbleed count, and a one interquartile range (IQR) poorer measures of continuous predictors (-1 IQR total brain volume, temporal-parietal lobe meta region of interest(ROI); +1 IQR WMH volume, global Aβ SUVR) on cross-sectional gait speed and change in gait speed adjusting for age, sex, education, study site, APOE e4, estimated intracranial volume, BMI, and cardiovascular risk factors. Cross-sectionally, slower gait speed outcome was associated with higher WMH volume, -3.38 cm/s (95%CI:-4.71, -2.04), infarct presence, -5.60 cm/s (-7.69, -3.51), microbleed count, -2.20 cm/s (-3.20, -0.91), smaller total brain volume, -9.26 cm/s (-12.1, -6.43), and smaller temporal-parietal lobe ROI -6.28 cm/s (-8.28, -4.28). Longitudinally, faster gait speed outcome decline was associated with higher WMH volume, -0.27 cm/s/year, (-0.51, -0.03) and higher global Aβ SUVR, -0.62 cm/s/year (-1.20, -0.03). Both cerebrovascular and AD pathology may contribute to mobility decline commonly seen with aging.
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http://dx.doi.org/10.1007/s11682-020-00435-yDOI Listing
January 2021

Correction to: An open-label, positron emission tomography study of the striatal D/D receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants.

Eur J Clin Pharmacol 2021 Jan 4. Epub 2021 Jan 4.

Section of High Resolution Brain PET, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1007/s00228-020-03071-zDOI Listing
January 2021

Associations Between Atrial Cardiopathy and Cerebral Amyloid: The ARIC-PET Study.

J Am Heart Assoc 2020 12 8;9(24):e018399. Epub 2020 Dec 8.

The Johns Hopkins University School of Medicine Baltimore MD.

Background Atrial fibrillation (AF) is a risk factor for cognitive decline, possibly from silent brain infarction. Left atrial changes in structure or function (atrial cardiopathy) can lead to AF but may impact cognition independently. It is unknown if AF or atrial cardiopathy also acts on Alzheimer disease-specific mechanisms, such as deposition of β-amyloid. Methods and Results A total of 316 dementia-free participants from the ARIC (Atherosclerosis Risk in Communities) study underwent florbetapir positron emission tomography, electrocardiography, and 2-dimensional echocardiography. Atrial cardiopathy was defined as ≥1: (1) left atrial volume index >34 mL/m; (2) P-wave terminal force >5000 µV×ms; and (3) serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) >250 pg/mL. Cross-sectional associations between global cortical β-amyloid (>1.2 standardized uptake value ratio) and adjudicated history of AF and atrial cardiopathy, each, were evaluated using multivariable logistic regression. Participants (mean age, 76 years) were 56% women and 42% Black individuals. Odds of elevated florbetapir standardized uptake value ratio were significantly increased among those with atrial cardiopathy (odds ratio, 1.81; 95% CI, 1.02-3.22) and doubled for those with enlarged left atrial volume index after adjustment for demographics/risk factors (95% CI, 1.04-4.61). There was no association between P-wave terminal force or NT-proBNP and elevated florbetapir standardized uptake value ratio, nor between AF and elevated standardized uptake value ratio. Conclusions Among healthy, nondemented community-dwelling older individuals, we report an association between atrial cardiopathy, left atrial volume index, and elevated brain amyloid, by positron emission tomography, without a similar association in individuals with AF. Potential limitations include reverse causation and survival bias. Ongoing work will help determine if changes in cardiac structure and function precede or occur simultaneously with amyloid deposition.
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http://dx.doi.org/10.1161/JAHA.120.018399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955392PMC
December 2020

Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome.

Brain Sci 2020 Nov 24;10(12). Epub 2020 Nov 24.

Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR) in knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR density as a proxy of mGluR expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluRs. The density and the distribution of mGluR were measured in two independent samples of men with FXS ( = 9) and typical development (TD) ( = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR expression showed that mGluR expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD.
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http://dx.doi.org/10.3390/brainsci10120899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760509PMC
November 2020

An open-label, positron emission tomography study of the striatal D/D receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants.

Eur J Clin Pharmacol 2021 May 16;77(5):717-725. Epub 2020 Nov 16.

Section of High Resolution Brain PET, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D/D receptor occupancy induced by the serotonin-dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25-6 mg.

Methods: Occupancy was measured at 4 and 23.5 h post-dose using the D/D receptor antagonist [C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel.

Results: Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D/D receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77-88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74-83%). Estimates of maximum obtainable receptor occupancy (O) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of O (EC) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC) and maximum plasma concentration (C) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort.

Conclusion: By extrapolating the observed single-dose D/D receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder.

Trial Registration: ClinicalTrials.gov NCT00805454 December 9, 2008.
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http://dx.doi.org/10.1007/s00228-020-03021-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032567PMC
May 2021

Neuronal insulin signaling and brain structure in nondemented older adults: the Atherosclerosis Risk in Communities Study.

Neurobiol Aging 2021 01 1;97:65-72. Epub 2020 Oct 1.

Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

We used plasma neuronal extracellular vesicles to examine how neuronal insulin signaling proteins relate cross-sectionally to brain structure in nondemented older adults with varying levels of cortical amyloid. Extracellular vesicles enriched for neuronal origin by anti-L1CAM immunoabsorption were isolated from plasma of Atherosclerosis Risk in Communities-Positron Emission Tomography study participants (n = 88; mean age: 77 years [standard deviation: 6]). Neuronal extracellular vesicle levels of phosphorylated insulin signaling cascade proteins were quantified. Brain volume and white matter hyperintensity (WMH) volume were assessed using 3T magnetic resonance imaging. After adjusting for demographic variables and extracellular vesicle marker Alix, higher levels of a neuronal insulin signaling composite measure were associated with lower WMH and greater temporal lobe volume. Secondary analyses found the levels of downstream protein kinases involved in cell survival (p70S6K) and tau phosphorylation/neuroinflammation (GSK-3β) to be most strongly associated with WMH and temporal lobe volume, respectively. Associations between neuronal insulin signaling and lower WMH volume were attenuated in participants with elevated cortical amyloid. These results suggest that enhanced neuronal proximal insulin signaling is associated with preserved brain structure in nondemented older adults.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736127PMC
January 2021

Dataset of quantitative structured office measurements of movements in the extremities.

Data Brief 2020 Aug 18;31:105876. Epub 2020 Jun 18.

Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.

A low-cost quantitative structured office measurement of movements in the extremities of people with Parkinson's disease [1,2] was performed on people with Parkinson's disease, multiple system atrophy, and age-matched healthy volunteers. Participants underwent twelve videotaped procedures rated by a trained examiner while connected to four accelerometers [1,2] generating a trace of the three location dimensions expressed as spreadsheets [3,4]. The signals of the five repetitive motion items [1,2] underwent processing to fast Fourier [5] and continuous wavelet transforms [6]. The dataset [7] includes the coding form with scores of the live ratings [1,2], the raw files [3], the converted spreadsheets [4], and the fast Fourier [5] and continuous wavelet transforms [6]. All files are unfiltered. The data also provide findings suitable to compare and contrast with data obtained by investigators applying the same procedure to other populations. Since this is an inexpensive procedure to quantitatively measure motions in Parkinson's disease and other movement disorders, this will be a valuable resource to colleagues, particularly in underdeveloped regions with limited budgets. The dataset will serve as a template for other investigations to develop novel techniques to facilitate the diagnosis, monitoring, and treatment of Parkinson's disease, other movement disorders, and other nervous and mental conditions. The procedure will provide the basis to obtain objective quantitative measurements of participants in clinical trials of new agents.
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http://dx.doi.org/10.1016/j.dib.2020.105876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334383PMC
August 2020

Mid- and Late-Life Leisure-Time Physical Activity and Global Brain Amyloid Burden: The Atherosclerosis Risk in Communities (ARIC)-PET Study.

J Alzheimers Dis 2020 ;76(1):139-147

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Physical activity (PA) may slow the development of dementia by reducing the accumulation of amyloid.

Objective: We tested the hypothesis that higher levels of leisure-time PA in mid- or late-life were associated with lower brain amyloid burden in late-life among 326 non-demented participants from the Atherosclerosis Risk in Communities Study of brain florbetapir positron emission tomography (ARIC-PET) ancillary.

Methods: Self-reported PA was quantified using a past-year recall, interviewer-administered questionnaire in mid-life (1987-1989, aged 45-64 years) and late-life (2011-2013, aged 67-89 years). Continuous PA estimates were classified as 1) any leisure-time PA participation (yes/no); 2) meeting the 2018 United States' PA guidelines (yes/no); and 3) per 1 standard deviation (SD) higher metabolic equivalent of task (MET) minutes per week (MET·min·wk-1). A brain magnetic resonance imaging scan with Florbetapir PET was performed in late-life. Adjusted odds ratios (OR) of elevated amyloid burden, defined as a global cortical standardized uptake value ratio (>1.2), compared to no elevated amyloid burden were estimated according to PA measures.

Results: Among the 326 participants (mean age: 76 years, 42% male, 41% Black), 52% had elevated brain amyloid burden. Mid-life leisure-time PA did not show a statistically significant lower odds of elevated late-life amyloid burden (OR = 0.71, 95% CI: 0.43-1.18). A 1 SD (970 MET. min. wk-1) higher PA level in mid-life was also not significantly associated withelevated amyloid burden (OR = 0.89, 95% CI: 0.69-1.15). Similar estimates were observed for meeting versus not meeting PA guidelines in both mid- and late-life.

Conclusion: Self-reported higher mid- and late-life leisure-time PA were not significantly associated with lower amyloid burden. Data show a trend of an association, which is, however, imprecise, suggesting replication in larger studies.
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http://dx.doi.org/10.3233/JAD-200152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011955PMC
May 2021

Association of Surgical Hospitalization with Brain Amyloid Deposition: The Atherosclerosis Risk in Communities-Positron Emission Tomography (ARIC-PET) Study.

Anesthesiology 2020 06;132(6):1407-1418

From the Departments of Neurology (K.A.W., R.F.G.) Radiology (D.F.W.) Anesthesiology (C.H.B.), Johns Hopkins School of Medicine, Baltimore, Maryland the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (R.F.G., J.C., A.R.S.) the Department of Neurology, Mayo Clinic, Rochester, Minnesota (D.S.K.) Department of Medicine, Division of Geriatrics, University of Mississippi Medical Center, Jackson, Mississippi (T.H.M.) the Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia (A.A.) the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri (Y.Z.).

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 β-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.
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http://dx.doi.org/10.1097/ALN.0000000000003255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540736PMC
June 2020

The association between midlife lipid levels and late-life brain amyloid deposition.

Neurobiol Aging 2020 08 15;92:73-74. Epub 2020 Apr 15.

Department of Epidemiology, The George Washington University, Milken Institute School of Public Health, Washington, DC, USA.

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340169PMC
August 2020

Beta-amyloid (Aβ) uptake by PET imaging in older HIV+ and HIV- individuals.

J Neurovirol 2020 06 8;26(3):382-390. Epub 2020 Apr 8.

Department of Neurology, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, 301 Building, Suite 2100, Baltimore, MD, 21224, USA.

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 (Aβ) deposition measured by [F] 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 [F] AV-45 PET imaging. [F] AV-45 binding to Aβ 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 Aβ deposition stratified by HIV serostatus or HAND stage. Although there was some evidence of increased Aβ 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.
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http://dx.doi.org/10.1007/s13365-020-00836-1DOI Listing
June 2020

Prediction of rapid amyloid and phosphorylated‐Tau accumulation in cognitively healthy individuals.

Alzheimers Dement (Amst) 2020 22;12(1):e12019. Epub 2020 Mar 22.

Laboratory of Behavioral Neuroscience National Institute on Aging National Institutes of Health Baltimore Maryland.

Objective: To test the hypothesis that among cognitively healthy individuals, distinct groups exist in terms of amyloid and phosphorylated-tau accumulation rates; that if rapid accumulator groups exist, their membership can be predicted by Alzheimer's disease (AD) risk factors, and that time points of significant increase in AD protein accumulation will be evident.

Methods: The analysis reports data from 263 individuals from the BIOCARD and 184 individuals from the Baltimore Longitudinal Study of Aging with repeated cerebrospinal fluid (CSF) and positron emission tomography (PET) sampling, respectively. We used latent class mixed-effect models to identify distinct classes of amyloid (CSF and PET) and p-Tau (CSF) accumulation rates and generalized additive modeling to investigate non-linear changes to AD biomarkers.

Results: For both amyloid and p-Tau latent class models we confirmed the existence of two separate classes: accumulators and non-accumulators. The accumulator and non-accumulator groups differed significantly in terms of baseline AD protein levels and slope of change. ε4 carrier status and episodic memory predicted amyloid class membership. Non-linear models revealed time points of significant increase in the rate of amyloid and p-Tau accumulation whereby ε4 carrier status associated with earlier age at onset of rapid accumulation.

Conclusions: The current analysis demonstrates the existence of distinct classes of amyloid and p-Tau accumulators. Predictors of class membership were identified but the overall accuracy of the models was modest, highlighting the need for additional biomarkers that are sensitive to early disease phenotypes.
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http://dx.doi.org/10.1002/dad2.12019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086102PMC
March 2020

Transcranial photoacoustic imaging of NMDA-evoked focal circuit dynamics in the rat hippocampus.

J Neural Eng 2020 04 8;17(2):025001. Epub 2020 Apr 8.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States of America. Laboratory of Computational Sensing and Robotics, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, United States of America.

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.
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http://dx.doi.org/10.1088/1741-2552/ab78caDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145727PMC
April 2020

Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.

J Cereb Blood Flow Metab 2020 08 16;40(8):1576-1585. Epub 2020 Feb 16.

Invicro and Division of Brain Sciences, Imperial College London, London, UK.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.
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http://dx.doi.org/10.1177/0271678X20905433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370374PMC
August 2020

Ethnic disparities in pain processing among healthy adults: μ-opioid receptor binding potential as a putative mechanism.

Pain 2020 04;161(4):810-820

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

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. This 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 participants. Participants completed questionnaires and two 90-minute high-resolution research tomograph positron emission tomography (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 striatum ([left]: F1,52 = 16.38, P < 0.001; [right]: F1,52 = 21.76, P < 0.001), bilateral dorsolateral prefrontal cortex ([left] F1,52 = 17.3, P < 0.001; [right]: F1,52 = 14.17, P < 0.001), bilateral subgenual anterior cingulate cortex ([left]: F1,52 = 10.4, P = 0.002; [right]: F1,52 = 12.91, P = 0.001), and right insula (F1,52 = 11.0, P = 0.002). However, there were no significant main effects of condition or ethnicity × 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 = 0.34-0.46, P range = 0.01-0.001). Results suggest that NHB individuals might have generally greater unoccupied MOR density than non-Hispanic white 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.
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http://dx.doi.org/10.1097/j.pain.0000000000001759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085427PMC
April 2020

Associations Between Left Ventricular Structure, Function, and Cerebral Amyloid: The ARIC-PET Study.

Stroke 2019 12 10;50(12):3622-3624. Epub 2019 Oct 10.

From the The Johns Hopkins University School of Medicine, Baltimore, MD (M.C.J., D.F.W., R.F.G.).

Background and Purpose- Cardiovascular disease is a known risk factor for cognitive decline, although the mechanisms remain unclear. We hypothesize that Aβ (β-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 Aβ (≥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.
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http://dx.doi.org/10.1161/STROKEAHA.119.027220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878182PMC
December 2019

Tau pathology in cognitively normal older adults.

Alzheimers Dement (Amst) 2019 Dec 6;11:637-645. Epub 2019 Sep 6.

Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.

Introduction: Tau pathology, a hallmark of Alzheimer's disease, is observed in the brains of virtually all individuals over 70 years.

Methods: Using F-AV-1451 (F-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 F-AV-1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume ( = -1.124, SE = 0.485, = .025) and a steeper decline in memory performance ( = -0.086, SE = 0.039, = .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.
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http://dx.doi.org/10.1016/j.dadm.2019.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732758PMC
December 2019

Transcranial Recording of Electrophysiological Neural Activity in the Rodent Brain Using Functional Photoacoustic Imaging of Near-Infrared Voltage-Sensitive Dye.

Front Neurosci 2019 9;13:579. Epub 2019 Aug 9.

Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, United States.

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 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 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 recording of brain activities through intact scalp, which would pave a way to its future translation in real time human brain imaging.
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http://dx.doi.org/10.3389/fnins.2019.00579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696882PMC
August 2019

High Availability of the α7-Nicotinic Acetylcholine Receptor in Brains of Individuals with Mild Cognitive Impairment: A Pilot Study Using F-ASEM PET.

J Nucl Med 2020 03 16;61(3):423-426. Epub 2019 Aug 16.

Department of Psychiatry, Johns Hopkins Medical Institutions, Baltimore, Maryland.

Emerging evidence supports a hypothesized role for the α7-nicotinic acetylcholine receptor (α7-nAChR) in the pathophysiology of Alzheimer's disease. F-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-F-fluorodibenzo[b,d]thiophene 5,5-dioxide) is a radioligand for estimating the availability of α7-nAChR in the brain in vivo with PET. In this cross-sectional study, 14 patients with mild cognitive impairment (MCI), a prodromal stage to dementia, and 17 cognitively intact, elderly controls completed F-ASEM PET. For each participant, binding in each region of interest was estimated using Logan graphical analysis with a metabolite-corrected arterial input function. Higher F-ASEM binding was observed in MCI patients than in controls across all regions, supporting higher availability of α7-nAChR in MCI. F-ASEM binding was not associated with verbal memory in this small MCI sample. These data support use of F-ASEM PET to examine further the relationship between α7-nAChR availability and MCI.
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http://dx.doi.org/10.2967/jnumed.119.230979DOI Listing
March 2020

Effect of STN DBS on vesicular monoamine transporter 2 and glucose metabolism in Parkinson's disease.

Parkinsonism Relat Disord 2019 07 16;64:235-241. Epub 2019 Apr 16.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

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 ± 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.
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http://dx.doi.org/10.1016/j.parkreldis.2019.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304230PMC
July 2019

The effect of ApoE ε4 on longitudinal brain region-specific glucose metabolism in patients with mild cognitive impairment: a FDG-PET study.

Neuroimage Clin 2019 28;22:101795. Epub 2019 Mar 28.

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Department of Nuclear Medicine, Peking University First Hospital, Beijing, China; Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.nicl.2019.101795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449776PMC
January 2020

Association of Head Injury with Brain Amyloid Deposition: The ARIC-PET Study.

J Neurotrauma 2019 09 23;36(17):2549-2557. Epub 2019 May 23.

Department of Neurology, Johns Hopkins University, Baltimore, Maryland.

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 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,  < 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.
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http://dx.doi.org/10.1089/neu.2018.6213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909743PMC
September 2019

Sex differences in the association between amyloid and longitudinal brain volume change in cognitively normal older adults.

Neuroimage Clin 2019 11;22:101769. Epub 2019 Mar 11.

Laboratory of Behavioral Neuroscience, National Institutes of Health, National Institute on Aging, Baltimore, MD, United States of America. Electronic address:

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 C-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 (β = -0.036, SE = 0.011, p = 0.001) and erc (β = -0.019, SE = 0.009, p = 0.045). Sex modified the association of PiB+ status and rates of volumetric declines in fusiform (β = -0.117, SE = 0.049, p = 0.019). PiB+ males had steeper rates of volumetric declines in phg (β = -0.051, SE = 0.013, p < 0.001) and erc (β = -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.
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http://dx.doi.org/10.1016/j.nicl.2019.101769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444285PMC
January 2020

Association of PET-measured myocardial flow reserve with echocardiography-estimated pulmonary artery systolic pressure in patients with hypertrophic cardiomyopathy.

PLoS One 2019 20;14(3):e0212573. Epub 2019 Mar 20.

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212573PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426216PMC
November 2019

Cognitive Reserve in Midlife is not Associated with Amyloid-β Deposition in Late-Life.

J Alzheimers Dis 2019 ;68(2):517-521

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

We examined associations between cognitive reserve and late-life amyloid-β 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.
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http://dx.doi.org/10.3233/JAD-180785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443418PMC
July 2020

Longitudinal evaluation of surrogates of regional cerebral blood flow computed from dynamic amyloid PET imaging.

J Cereb Blood Flow Metab 2020 02 12;40(2):288-297. Epub 2019 Feb 12.

Laboratory of Behavioral Neuroscience, National Institute on Aging (NIA), Baltimore, USA.

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 computed from dynamic C-Pittsburgh compound B (PiB) PET can serve as surrogates of rCBF computed from O-HO-PET. 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 . Correlations between rates of change were lower (IQR 0.22-0.50 for EA, 0.25-0.55 for ). 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 were lower among amyloid+ individuals; EA and were lower among males. Regional PiB-based measures, in particular , 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.
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http://dx.doi.org/10.1177/0271678X19830537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370613PMC
February 2020

PET imaging of dopamine release in the frontal cortex of manganese-exposed non-human primates.

J Neurochem 2019 07 26;150(2):188-201. Epub 2019 Mar 26.

Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

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 [ C]-FLB457 positron emission tomography with amphetamine challenge to measure DAR in Cynomolgus macaques. Animals received [ 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.
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http://dx.doi.org/10.1111/jnc.14681DOI Listing
July 2019

Vestibular Function and Beta-Amyloid Deposition in the Baltimore Longitudinal Study of Aging.

Front Aging Neurosci 2018 11;10:408. Epub 2018 Dec 11.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, United States.

Beta-amyloid (Aβ) plaque deposition is a key feature of Alzheimer's disease (AD), and occurs years before the onset of symptoms. Aβ plaque deposition has been shown to be present in ~30% of cognitively normal older adults using amyloid C-11 labeled Pittsburgh Compound B (C-PiB) Positron Emission Tomography (PET) imaging. Prior studies have reported a link between reduced vestibular function and poorer cognition in healthy older adults. It is unknown whether vestibular impairment occurs in association with AD pathology among individuals in the preclinical phase of AD, which could contribute to the observed association between vestibular and cognitive function in healthy older adults. Using the Baltimore Longitudinal Study of Aging (BLSA), we analyzed the association between a comprehensive set of vestibular function measures and PiB status in 98 healthy participants with a mean age of 77.3 (±8.26). We did not observe a significant relationship between any vestibular function measure and PiB status in cognitively-intact older adults in the BLSA. This finding suggests that Aβ deposition does not explain the observed association between reduced vestibular function and poorer cognition in healthy older adults.
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http://dx.doi.org/10.3389/fnagi.2018.00408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297212PMC
December 2018