This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were observed in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 +/- 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = -0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.

Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.

Structure and function of the blood–brain barrier

A theoretical model of blood-brain exchange is developed and a procedure is derived that can be used for graphing multiple-time tissue uptake data and determining whether a unidirectional transfer process was dominant during part or all of the experimental period. If the graph indicates unidirectionality of uptake, then an influx constant (Ki) can be calculated. The model is general, assumes linear transfer kinetics, and consists of a blood-plasma compartment, a reversible tissue region with an arbitrary number of compartments, and one or more irreversible tissue regions. The solution of the equations for this model shows that a graph of the ratio of the total tissue solute concentration at the times of sampling to the plasma concentration at the respective times (Cp) versus the ratio of the arterial plasma concentration-time integral to Cp should be drawn. If the data are consistent with this model, then this graph will yield a curve that eventually becomes linear, with a slope of Ki and an ordinate intercept less than or equal to the vascular plus steady-state space of the reversible tissue region.

/pdf/graphical-evaluation-of-blood-to-brain-transfer-constants-2e29v1hms2.pdf

Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data:

We describe a standard set of quantity names and symbols related to the estimation of kinetic parameters from dynamic contrast-enhanced T(1)-weighted magnetic resonance imaging data, using diffusable agents such as gadopentetate dimeglumine (Gd-DTPA). These include a) the volume transfer constant K(trans) (min(-1)); b) the volume of extravascular extracellular space (EES) per unit volume of tissue v(e) (0 < v(e) < 1); and c) the flux rate constant between EES and plasma k(ep) (min(-1)). The rate constant is the ratio of the transfer constant to the EES (k(ep) = K(trans)/v(e)). Under flow-limited conditions K(trans) equals the blood plasma flow per unit volume of tissue; under permeability-limited conditions K(trans) equals the permeability surface area product per unit volume of tissue. We relate these quantities to previously published work from our groups; our future publications will refer to these standardized terms, and we propose that these be adopted as international standards.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291522-2586%28199909%2910%3A3%3C223%3A%3AAID-JMRI2%3E3.0.CO%3B2-S

Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols.

Rats were implanted with 0.3-mm-diameter dialysis tubing through the hippocampus and subsequently perfused with Ringer's solution at a flow rate of 2 microliter/min. Samples of the perfusate representing the extracellular fluid were collected over 5-min periods and subsequently analyzed for contents of the amino acids glutamate, aspartate, glutamine, taurine, alanine, and serine. Samples were collected before, during, and after a 10-min period of transient complete cerebral ischemia. The extracellular contents of glutamate and aspartate were increased, respectively, eight- and threefold during the ischemic period; the taurine concentration also was increased 2.6-fold. During the same period the extracellular content of glutamine was significantly decreased (to 68% of the control value), whereas the concentrations of alanine and serine did not change significantly during the ischemic period. The concentrations of gamma-aminobutyric acid (GABA) were too low to be measured reliably. It is suggested that the large increase in the content of extracellular glutamate and aspartate in the hippocampus induced by the ischemia may be one of the causal factors in the damage to certain neurons observed after ischemia.

Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis

The transport of α-aminoisobutyric acid (AIB), N-methyl-AIB (MeAIB), and diethylenetriaminepentaacetic acid (DTPA) from blood to brain was measured over different experimental periods in eight regi...

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1983.2

Transport of α-Aminoisobutyric Acid across Brain Capillary and Cellular Membranes

Ventriculocisternal perfusions with five isotopically labeled drugs were performed in the rhesus monkey and the resultant tissue diffusion concentration profiles in caudate nucleus were analyzed. The periventricular distribution space with respect to perfusate concentration was measured and expressed as microliters per 100 mg wet weight: hydroxyurea = 56; methotrexate = 27; thiotepa = 28; 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) = 64 and cytosine arabinoside greater than 170. The apparent diffusion constants in caudate nucleus were determined for hydroxyurea and methotrexate (2.0 and 1.2 X 10(-6) cm2/sec, respectively); capillary permeability expressed as an extracellular space-transcapillary exchange half-time was estimated to be greater than 2 hours for both compounds. The extracellular fluid-transcapillary half-time was measured for thiotepa and BCNU (1.0 and 0.8 minute, respectively). Cytosine arabinoside continued to be concentrated by periventricular caudate nucleus during the course of perfusion; perfusate clearance measurements suggest a low capillary permeability. The apparent parenchymal diffusion constant and the capillary permeability of a drug in brain are discussed and are considered useful parameters for predicting drug levels after intrathecal administration.

Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion.

In Alzheimer's disease, the neuritic or senile amyloid plaques in hippocampus and association cortex, the diffuse plaques in brain areas such as the cerebellum and sensorimotor cortex, and the amyloid deposits in the walls of pial and parenchymal blood vessels are mainly composed of amyloid beta-peptides. In the present study, either soluble 40-residue amyloid beta-peptide radiolabeled with 125I (I-sAbeta) or [14C]polyethylene glycol ([14C]PEG, a reference material) was briefly infused into one lateral ventricle of normal rats. By 3.5 min, 30% of the I-sAbeta was cleared from ventricular CSF into blood; another 30% was removed over the next 6.5 min. No [14C]PEG was lost from the CSF-brain system during the first 5 min, and only 20% was cleared by 10 min. Much of the I-sAbeta that reached the subarachnoid space was retained by pial arteries and arterioles. Virtually no I-sAbeta was found in brain. The clearance of amyloid beta-peptides from the CSF-brain system, reported herein for normal rats, may be reduced in Alzheimer's disease, thus contributing to amyloid deposition in cerebral tissue and blood vessels.

Joseph D. Fenstermacher

Papers

Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data:

Transport of α-Aminoisobutyric Acid across Brain Capillary and Cellular Membranes

Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion.

Fate of Cerebrospinal Fluid‐Borne Amyloid β‐Peptide: Rapid Clearance into Blood and Appreciable Accumulation by Cerebral Arteries

Methods for Quantifying the transport of drugs across brain barrier systems.