Mark A. Mintun's research while affiliated with Avid Radiopharmaceuticals and other places
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Publications (161)
Background
Deep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer's Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the class...
Importance
Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic...
We propose a new approach, called as functional deep neural network (FDNN), for classifying multidimensional functional data. Specifically, a deep neural network is trained based on the principal components of the training data which shall be used to predict the class label of a future data function. Unlike the popular functional discriminant analy...
We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive m...
The process of identifying suitable genome-wide association (GWA) studies and formatting the data to calculate multiple polygenic risk scores on a single genome can be laborious. Here, we present a centralized polygenic risk score calculator currently containing over 250,000 genetic variant associations from the NHGRI-EBI GWAS Catalog for users to...
We report on the initial 17 (11 male:6 female) brain autopsies from across Europe and the United States in the Parkinson's Progression Markers Initiative (PPMI). Clinical diagnoses were Parkinson's disease (n = 15), multiple system atrophy (n = 1), and Dementia with Lewy bodies (n = 1); average age of death = 72 ± 8 yr. Cognitive assessment at last...
Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological ch...
Exploring individual hallmarks of brain ageing is important. Here, we propose the age-related glucose metabolism pattern (ARGMP) as a potential index to characterize brain ageing in cognitively normal (CN) elderly people. We collected 18F-fluorodeoxyglucose (18F-FDG) PET brain images from two independent cohorts: the Alzheimer’s Disease Neuroimagin...
The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we ai...
Importance:
One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.
Objective:...
Heterogeneity of brain diseases is a challenge for precision diagnosis/prognosis. We describe and validate Smile-GAN (SeMI-supervised cLustEring-Generative Adversarial Network), a semi-supervised deep-clustering method, which examines neuroanatomical heterogeneity contrasted against normal brain structure, to identify disease subtypes through neuro...
Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of A...
Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer’s diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer’s pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET wer...
A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic...
Causal Structure Discovery (CSD) is the problem of identifying causal relationships from large quantities of data through computational methods. With the limited ability of traditional association-based computational methods to discover causal relationships, CSD methodologies are gaining popularity. The goal of the study was to systematically exami...
Background:
The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All par...
Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and...
Objective:
To determine the feasibility, safety and tolerability of lumbar punctures (LPs) in research participants with early Parkinson disease (PD), subjects without evidence of dopaminergic deficiency (SWEDDs) and healthy volunteers (HC).
Background:
Cerebrospinal fluid (CSF) analysis is becoming an essential part of the biomarkers discovery...
Tauopathy is a hallmark pathology of Alzheimer's disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET li...
Background:
Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively.
Methods:
Amyloid depositi...
Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and mul...
Importance
Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non–AD dementia.Objective
To use individual participant data meta-analysis to estimat...
RATIONALE: Synaptic dopamine (DA) release induced by amphetamine or other experimental manipulations can displace [ C]raclopride (RAC*) from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine release at striatal synapses under some conditions but not others, allowing a more naturalistic assessment of presyna...
Although amyloid imaging with PiB-PET ([C-11]Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In...
Background:
Published appropriate use criteria (AUC) describe patients for whom amyloid positron emission tomography (PET) might be most useful. This study compared the impact of amyloid PET on diagnosis and management in subjects likely to either meet or not meet AUC.
Methods:
Physicians provided a provisional diagnosis and management plan for...
Appropriate use criteria (AUC; Johnson et al, 2013) provide guidelines for selecting patients for whom amyloid PET could be useful. This study evaluated the impact of amyloid PET on diagnosis/management in patients likely to meet AUC.
Methods:
We examined 229 cases from a completed study of florbetapir amyloid PET (FBP-PET) in patients with a cogni...
BACKGROUND: Several lines of evidence suggest that dopamine (DA)-influenced neuronal pathways may malfunction in Tourette Syndrome (TS). A dopamine-responsive abnormality of brain function in TS could be either presynaptic or postsynaptic. Some PET studies support the hypothesis of presynaptic abnormalities in levodopa uptake, dopamine synthesis, o...
Background: Alzheimer Disease is characterized by cerebral atrophy and dementia, with deposition of amyloid plaques. In addition, white matter injury seen by diffusion imaging is associated with dementia (1). Importantly, in some individuals, amyloid plaque deposition precedes the onset of dementia (2) as evidenced by uptake of Pittsburgh Compound...
To investigate factors, including cognitive and brain reserve, which may independently predict prevalent and incident dementia of the Alzheimer type (DAT) and to determine whether inclusion of identified factors increases the predictive accuracy of the CSF biomarkers Aβ(42), tau, ptau(181), tau/Aβ(42), and ptau(181)/Aβ(42).
Logistic regression iden...
Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-beta42 (Alphabeta42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent (11)C-Pittsburgh compound B ((11)C-PiB), a biomarker...
Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help t...
See a preprint online at:
Black KJ, Piccirillo ML, Koller JM, Hseih T, Wang L et al. (2013) Levodopa-stimulated dopamine release in Tourette syndrome. PeerJ PrePrints 1:e30v1 http://dx.doi.org/10.7287/peerj.preprints.30v1
Conscious recall of past events which have specific temporal and spatial contexts, termed episodic memory, is mediated by a system of interrelated brain regions. In Alzheimer's disease (AD) this system breaks down, resulting in an inability to recall events from the immediate past. Studies of normal human auditory-verbal short-term memory suggest t...
Beta-amyloid (Abeta) plaques are the hallmark of Alzheimer disease (AD). A PET imaging tracer that binds to Abeta plaques in vivo, N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]PIB for "Pittsburgh Compound-B"), has significantly higher binding in subjects diagnosed with dementia of the Alzheimer type (DAT) compared to n...
The effect of depression on the hippocampus has become the focus of a number of structural and functional neuroimaging studies. In the past two decades, advances in neuroimaging techniques now allow the examination of subtle changes in both regional structure and function that are associated with the pathophysiology of depression. Many studies usin...
The effect of depression on the hippocampus has become the focus of a number of structural and functional neuroimaging studies. In the past two decades, advances in neuroimaging techniques now allow the examination of subtle changes in both regional structure and function that are associated with the pathophysiology of depression. Many studies usin...
The amygdala has a central role in processing emotions, particularly fear. During functional magnetic resonance imaging (fMRI) amygdala activation has been demonstrated outside of conscious awareness using masked emotional faces.
We applied the masked faces paradigm to patients with major depression (n = 11) and matched control subjects (n = 11) du...
Abundant in vitro and animal model data suggest the postsynaptic gamma-aminobutyric acid receptor type A (GABA(A)-R) is an important target for volatile general anesthetics, but the relevance of these models is untested in humans. Because benzodiazepines have also been shown to act via a specific GABA(A)-R site, they provide sensitive probes for th...
Coupling of cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO(2)) in physiologically activated brain states remains the subject of debates. Recently it was suggested that CBF is tightly coupled to oxidative metabolism in a nonlinear fashion. As part of this hypothesis, mathematical models of oxygen delivery to the brain have be...
Purpose:
Locoregional tumor control for locally advanced cancers with radiation therapy has been unsatisfactory. This is in part associated with the phenomenon of tumor hypoxia. Assessing hypoxia in human tumors has been difficult due to the lack of clinically noninvasive and reproducible methods. A recently developed positron emission tomography...
This study takes advantage of continuing advances in the precision of magnetic resonance imaging (MRI) to quantify hippocampal volumes in a series of human subjects with a history of depression compared with controls. We sought to test the hypothesis that both age and duration of past depression would be inversely and independently correlated with...
Individuals infected with HIV are at risk to develop cognitive impairment during the course of their disease. Although many patients develop an HIV-associated dementia, others may develop the less severe minor cognitive motor disorder (MCMD). In this study, relative cerebral blood flow was measured with PET imaging in HIV+ MCMD patients, HIV+ contr...
The serotonin (5-HT) neurotransmitter system, which has a widespread distribution in the central nervous system, has been implicated in regulating mood and many human behaviors. There is evidence from postmortem human studies and limited information from prior in vivo studies to support a decline in 5-HT2A receptor density with aging. We examined n...
Hypofrontality is a common but not invariable finding in schizophrenia. Inconsistencies in the literature may reflect, in part, the fact that abnormal physiological responses in the prefrontal cortex are best identified under conditions that place well-specified functional demands on this region.
The authors studied eight patients with schizophreni...
We asked whether the altered cerebral vasculature associated with essential hypertension might dampen or redirect the regional cerebral blood flow (rCBF) response to cognitive work. Relative rCBF was assessed with [(15)O]water positron emission tomography during a working memory task, a memory span task, and two perceptual control tasks. Unmedicate...
Am J Hypertens (1998) 11, 134A–134A; doi: 10.1016/S0895-7061(97)91210-3
G001: Cerebral blood flow in hypertensives: An initial report of reduced and compensatory blood flow responses during performance of two cognitive tasks
J.R. Jennings, M.F. Muldoon, C. Ryan, M. Mintun, C. Meltzer, D. Townsend, K. Sutton-Tyrrell, A.P. Shapiro and S.B. Manuck
Using a pharmacological probe, procaine hydrochloride, the authors elicited consistent and selective activation of anterior limbic and paralimbic structures in normal human volunteers as documented by (H2O)-O-15 positron emission tomography. This activation was associated with a range of emotional, somatic, and visceral experiences, often similar t...
The purpose of this study was to examine regional cerebral blood flow using positron emission tomography (PET) during the performance of tasks related to visual confrontation naming. Ten healthy, young participants were scanned twice in each of 5 conditions; blood flow was measured using standard PET [15O]-water technology. Two major findings have...
Although sleep is characterized by relative behavioral inactivity, cortical activity is known to cycle in well-defined periods across this state. Cognitive function during sleep has been difficult to define, although disturbances in sleep are known to result from, and to cause, various human pathologies, including neuropsychiatric disorders. Assess...
Using a pharmacological probe, procaine hydrochloride, the authors elicited consistent and selective activation of anterior limbic and paralimbic structures in normal human volunteers as documented by H215O positron emission tomography. This activation was associated with a range of emotional, somatic, and visceral experiences, often similar to tho...
Attentional deficits are a prominent aspect of cognitive dysfunction in schizophrenia. The anterior cingulate gyrus is proposed to be an important component of frontal attentional control systems. Structural and functional abnormalities have been reported in this region in schizophrenia, but their relationship to attentional deficits is unknown. Th...
Positron-emitting radiopharmaceuticals are required for positron emission tomography (PET), an imaging technology, and the standards of purity for these drugs are defined by the USP. Flumazenil C 11 Injection is a radiopharmaceutical for PET imaging of benzodiazepine (BZP) receptor binding in the living human brain. ["CjFlumazenil has been shown to...
Rapid eye movement (REM) sleep is a behavioral state characterized by cerebral cortical activation with dreaming as an associated behavior. The brainstem mechanisms involved in the generation of REM sleep are well-known, but the forebrain mechanisms that might distinguish it from waking are not well understood. We report here a positron emission to...
Brain regions responsive to novelty, without awareness, were mapped in humans by positron emission tomography. Participants performed a simple reaction-time task in which all stimuli were equally likely but, unknown to them, followed a complex sequence. Measures of behavioral performance indicated that participants learned the sequences even though...
Although previous studies have provided some insight into the pharmacologic aspects of nitrous oxide analgesia, the neural circuits mediating its antinociceptive effect remain relatively unexplored. Position emission tomography was used in nine volunteers to identify the loci of nitrous oxide-modulated cerebral responses to a peripheral noxious sti...
The purpose of this study was to examine changes in regional cerebral blood flow (rCBF) using positron emission tomography (PET) during overt word and nonword reading tasks to determine structures involved in semantic processing. Ten young, healthy, right-handed subjects were scanned 12 times, twice in each of six specific conditions. Blood flow wa...
Recent positron emission tomography (PET) studies have demonstrated areas of pain processing in the human brain. Given the inhibitory effects of opioids on neuronal activity, we predicted that fentanyl's analgesic effects would be associated with suppression of pain-evoked responses in these distinct brain areas. To test this, PET was used to measu...
Changes in regional cerebral blood flow (rCBF), associated with performance of an auditory verbal supraspan memory task, were studied in eight remitted DSM-III-R schizophrenic patients and eight pair-wise matched normal controls. Four positron emission tomography (PET) scans, using the [15O]-H2O technique, were acquired: two while subjects fixated...
The purpose of this study was to examine changes in regional cerebral blood flow (rCBF) using positron emission tomography (PET) during overt word and nonword reading tasks to determine structures involved in semantic processing. Ten young, healthy, right-handed subjects were scanned 12 times, twice in each of six specific conditions. Blood flow wa...
This chapter examines the usefulness of [11C]WAY 100635 for the in vivo quantitation of 5-HT1A receptor binding. Positron emission tomography (PET) data are acquired in monkeys after high specific activity injections alone and after pre-injection with either an agonist or antagonist. The cerebellar and blocking data were not well fit with a two-com...
Alzheimer's disease (AD) patients show normal patterns of regional cerebral blood flow during performance of subspan verbal memory tasks, but appear to allocate new brain regions when performing supraspan recall tasks. To understand the relationships among these interconnected brain regions, their functional connectivity was considered using princi...
Human behavioral studies have shown that nitrous oxide, in subanesthetic concentrations, impairs psychomotor function, cognitive performance, and learning and memory processes. However, the cerebral mechanisms of such effects remain unknown. Positron emission tomography (PET) was used to map the brain areas associated with nitrous oxide effects. Re...
Defects of glucose transport and phosphorylation may underlie insulin resistance in obesity and non-insulin-dependent diabetes mellitus (NIDDM). To test this hypothesis, dynamic imaging of 18F-2-deoxy-glucose uptake into midthigh muscle was performed using positron emission tomography during basal and insulin-stimulated conditions (40 mU/m2 per min...
Positron emission tomography (PET) is a noninvasive imaging technique that can be used to observe drug actions on human brain in vivo. We used 15O-water PET scanning in six volunteers to examine the effects on regional cerebral activity as reflected by regional cerebral blood flow (rCBF) of a small intravenous bolus of fentanyl. rCBF was compared b...
Positron emission tomography (PET) is a noninvasive imaging technique that can be used to observe drug actions on human brain in vivo.We used¹⁵ O-water PET scanning in six volunteers to examine the effects on regional cerebral activity as reflected by regional cerebral blood flow (rCBF) of a small intravenous bolus of fentanyl. rCBF was compared be...
Serotonergic system abnormalities have been implicated in major depression, suicide, violence, alcoholism, and other psychopathologies. The prolactin response to fenfluramine has been widely used as a neuroendocrine probe to study brain serotonin responsivity. We have extended this methodology by using the positron emission tomography (PET) 18F-flu...
Conscious recall of past events that have specific temporal and spatial contexts, termed episodic memory, is mediated by a system of interrelated brain regions. In Alzheimer's disease (AD) this system breaks down, resulting in an inability to recall events from the immediate past. Using subtraction techniques with PET-acquired images of regional ce...