P4‐067: Novel high‐field mri applied to the early detection of Alzheimer's disease‐related pathology
Tracy PorchakTricia A. Thornton‐WellsBrandon A. AllyErin HusseySeth A. SmithJ. O. CobbAdrienne N. DulaSwati RaneBrian T. WelchAdam W. AndersonJohn C. GoreManus J. Donahue
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Beta-amyloid plaques and tau-containing neurofibrillary tangles are recognized biomarkers of Alzheimer's disease (AD) onset and progression, yet hemodynamic and/or metabolic modulations that may precede such changes are currently debated. Importantly, detecting and evaluating early-stage pathogenesis is critical to characterizing disease etiology and guiding treatments intended to prevent irreversible tissue damage. Magnetic resonance imaging (MRI) poses potential for investigating pathological biomarkers owing to its variety of noninvasive contrast mechanisms. Therefore, we have initiated a collaborative effort between imaging physicists, neuropsychologists, and geneticists with the aim of identifying hemodynamic, neurochemical, and metabolic biomarkers in preclinical AD using novel MRI approaches at intermediate (3T) and high (7T) magnetic field. This study has been divided into three stages with distinct benchmarks for success: (i) to optimize high-field protocols for at-risk (APOE-e4 carrier or family history) AD populations, (ii) to measure neurochemical and hemodynamic parameters in preclinical at-risk populations (APOE-e4 carrier or family history), and (iii) to evaluate imaging biomarkers in patients with clinical AD. In addition to structural scans, novel approaches with AD-relevant contrasts have been implemented: (1) arterial spin labeling (cerebral blood flow), (2) vascular-space-occupancy (cerebral blood volume), (3) T1-? (beta-amyloid), (4) chemical-exchange-saturation-transfer (neurochemicals), (5) spontaneous blood-oxygenation-level-dependent (functional-connectivity), (6) susceptibility weighting (microbleeds) and (7) T2-relaxation-under-spin-tagging (oxygen extraction fraction). The imaging choices were motivated by (i) uniqueness, i.e. approaches that have not been robustly tested in AD and (ii) approaches that generate specific contrasts for parameters hypothesized to be implicated in early-stage AD. This study represents an active trial with a target enrollment of 10 patients per month. We have implemented the above approaches, performed quality control measurements in healthy populations and are actively enrolling at-risk volunteers with mild cognitive impairment. Fig. 1 shows representative images from the AD protocol; pilot data from at-risk subjects, in the context of healthy volunteers, will be discussed. A novel high-field MRI protocol has been implemented for early detection of hemodynamic, neurochemical and metabolic changes that may precede structural or clinical changes in AD. This ongoing work is a multi-departmental effort and is expected to provide mechanistic clues regarding early-stage functional changes in AD. Representative images from novel imaging approaches employed in AD protocol. (a) 7T high-spatial resolution (1.6 mm) functional connectivity mapping, (b) 3.OT noninvasive cerebral blood flow imaging with arterial spin labeling. 7T high-spatial resolution (0.75 mm) structural imaging, and (d) 7T high spatial resolution (0.5 mm)susceptility weighted imaging.Keywords:
Neurochemical
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Electrochemistry is one of the most advanced techniques for monitoring neurochemical activities in the living brain because electrochemical approaches bear the advantageous features of high spatial and temporal resolutions, which facilitate its tremendous potential in investigating the highly spatially heterogeneous brain system and the fast dynamics of neurochemical activities. On the other hand, since brain is the most complicated organ in the sense of its numerous kinds of neurochemical species, high selectivity is always required for any analytical methods that approach the brain. In this review, we will discuss various electrochemical methodologies to achieve selective detection of neurochemicals in mammalian brain and the strategies developed mainly by our group towards selective monitoring of both electrochemically active and inactive neurochemicals. At the end, we will discuss possible solutions towards brain mapping of neurochemical species and combination of neurochemical detection strategy with electrophysiology as the direction of future development of electroanalysis in living brain.
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The interpretation of neurochemical studies of attention deficit disorder (ADD) with hyperactivity is complicated by the variability in diagnosis and by the limitations of single neurochemical measures--whose levels may be compensated by chronic feedback mechanisms. This article reviews previous neurochemical studies of ADD and proposes the use of single-dose neurochemical probes. Administration of a provocative agent with subsequent sequential measures of plasma levels of neurotransmitters, their metabolites, and hormones may help define the responsivity of neurochemical systems. Blood levels of drugs and neurotransmitters following single doses of methylphenidate and clonidine are studied as a strategy to explore the responsivity of dopaminergic and noradrenergic mechanisms in ADD.
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In neuroscience, the consequences of optogenetic manipulation are often studied using in vivo electrophysiology and by observing behavioral changes induced by light stimulation in genetically targeted rodents. In contrast, reports on the in vivo neurochemical effects of optogenetic stimulation are scarce despite the improving quality of analytical techniques available to monitor biochemical compounds involved in neurotransmission. This intriguing lack of neurochemical information suggests the existence of unknown or misunderstood factors hampering the expected rise of a novel specialty putatively be termed "neurochemical optogenetics".
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