Basal forebrain volume reliably predicts the cortical spread of Alzheimer's degeneration.

Alzheimer's disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer's degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer's disease using two independent samples of the Alzheimer's Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-ß and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-ß moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer's disease pathogenesis.

Free Water in White Matter Differentiates MCI and AD From Control Subjects.

Recent evidence shows that neuroinflammation plays a role in many neurological diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD), and that free water (FW) modeling from clinically acquired diffusion MRI (DTI-like acquisitions) can be sensitive to this phenomenon. This FW index measures the fraction of the diffusion signal explained by isotropically unconstrained water, as estimated from a bi-tensor model. In this study, we developed a simple but powerful whole-brain FW measure designed for easy translation to clinical settings and potential use as a priori outcome measure in clinical trials. These simple FW measures use a "safe" white matter (WM) mask without gray matter (GM)/CSF partial volume contamination (WM safe) near ventricles and sulci. We investigated if FW inside the WM safe mask, including and excluding areas of white matter damage such as white matter hyperintensities (WMHs) as shown on T2 FLAIR, computed across the whole white matter could be indicative of diagnostic grouping along the AD continuum. After careful quality control, 81 cognitively normal controls (NC), 103 subjects with MCI and 42 with AD were selected from the ADNIGO and ADNI2 databases. We show that MCI and AD have significantly higher FW measures even after removing all partial volume contamination. We also show, for the first time, that when WMHs are removed from the masks, the significant results are maintained, which demonstrates that the FW measures are not just a byproduct of WMHs. Our new and simple FW measures can be used to increase our understanding of the role of inflammation-associated edema in AD and may aid in the differentiation of healthy subjects from MCI and AD patients.

Immunotherapy with ponezumab for probable cerebral amyloid angiopathy.

OBJECTIVE: Cerebral amyloid angiopathy (CAA) is caused by cerebrovascular deposition of ß-amyloid fragments leading to cerebrovascular dysfunction and other brain injuries. This phase 2, randomized, double-blind trial in patients with probable CAA assessed the efficacy and safety of ponezumab, a novel monoclonal antibody against Aß 1-40. METHODS: Thirty-six participants aged 55-80 years with probable CAA received intravenous placebo (n = 12) or ponezumab (n = 24). The change from baseline to Days 2 and 90 in cerebrovascular reactivity (CVR) was measured in the visual cortex as the natural log of the rising slope of the BOLD fMRI response to a visual stimulus. Safety and tolerability were also assessed. RESULTS: The mean change from baseline to Day 90 was 0.817 (ponezumab) and 0.958 (placebo): a mean ratio of 0.852 (90% CI 0.735-0.989) representing a trend towards reduced CVR in the ponezumab group. This trend was not present at Day 2. There was one asymptomatic occurrence of amyloid-related imaging abnormality-edema in the ponezumab group. The total number of new cerebral microbleeds from baseline to day 90 did not differ between groups. The ponezumab group had a participant with nonfatal new cerebral hemorrhage with aphasia and a participant with subdural hemorrhage that site investigators deemed to be nondrug related. In the placebo group one participant had a fatal intracerebral hemorrhage and one participant had migraine with aura. INTERPRETATION: Ponezumab was safe and well-tolerated. The ponezumab group showed a trend towards treatment effect at Day 90 that was opposite to the hypothesized direction. The prespecified efficacy criteria were thus not met.

The role of fMRI in drug development.

Functional magnetic resonance imaging (fMRI) has been known for over a decade to have the potential to greatly enhance the process of developing novel therapeutic drugs for prevalent health conditions. However, the use of fMRI in drug development continues to be relatively limited because of a variety of technical, biological, and strategic barriers that continue to limit progress. Here, we briefly review the roles that fMRI can have in the drug development process and the requirements it must meet to be useful in this setting. We then provide an update on our current understanding of the strengths and limitations of fMRI as a tool for drug developers and recommend activities to enhance its utility.

Dynamic-contrast-enhanced-MRI with extravasating contrast reagent: rat cerebral glioma blood volume determination.

The accurate mapping of the tumor blood volume (TBV) fraction (vb) is a highly desired imaging biometric goal. It is commonly thought that achieving this is difficult, if not impossible, when small molecule contrast reagents (CRs) are used for the T1-weighted (Dynamic-Contrast-Enhanced) DCE-MRI technique. This is because angiogenic malignant tumor vessels allow facile CR extravasation. Here, a three-site equilibrium water exchange model is applied to DCE-MRI data from the cerebrally-implanted rat brain U87 glioma, a tumor exhibiting rapid CR extravasation. Analyses of segments of the (and the entire) DCE data time-course with this "shutter-speed" pharmacokinetic model, which admits finite water exchange kinetics, allow TBV estimation from the first-pass segment. Pairwise parameter determinances were tested with grid searches of 2D parametric error surfaces. Tumor blood volume (vb), as well as ve (the extracellular, extravascular space volume fraction), and Ktrans (a CR extravasation rate measure) parametric maps are presented. The role of the Patlak Plot in DCE-MRI is also considered.

Dynamic MRI using iron oxide nanoparticles to assess early vascular effects of antiangiogenic versus corticosteroid treatment in a glioma model.

The vascular effects of antiangiogenic treatment may pose problems for evaluating brain tumor response based on contrast-enhanced magnetic resonance imaging (MRI). We used serial dynamic contrast-enhanced MRI at 12 T to assess vascular responses to antiangiogenic versus steroid therapy. Athymic rats with intracerebral U87MG human glioma (n=17) underwent susceptibility-weighted perfusion MRI with ferumoxytol, a solely intravascular ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle, followed by T1-weighted dynamic gadodiamide-enhanced MRI to measure vascular permeability. Rats were imaged before and after 24, 48, and 72 h of treatment with the antiangiogenic agent bevacizumab or the corticosteroid dexamethasone. Contrast agent extravasation was seen rapidly after gadodiamide, but not with ferumoxytol administration. Bevacizumab significantly decreased the blood volume and decreased permeability in tumors as determined by increased time-to-peak enhancement. A single dose of 45 mg/kg bevacizumab resulted in changes analogous to dexamethasone given in an extremely high dose (12 mg/kg per day), and was significantly more effective than dexamethasone at 2 mg/kg per day. We conclude that dynamic perfusion MRI measurements with ferumoxytol USPIO to assess cerebral blood volume, along with dynamic gadodiamide-enhanced MR to assess vascular permeability, hold promise in more accurately detecting therapeutic responses to antiangiogenic therapy.

Influence of atmospheric and sea-surface corrections on retrieval of bottom depth and reflectance using a semi-analytical model: a case study in Kaneohe Bay, Hawaii.

Hyperspectral instruments provide the spectral detail necessary for extracting multiple layers of information from inherently complex coastal environments. We evaluate the performance of a semi-analytical optimization model for deriving bathymetry, benthic reflectance, and water optical properties using hyperspectral AVIRIS imagery of Kaneohe Bay, Hawaii. We examine the relative impacts on model performance using two different atmospheric correction algorithms and two different methods for reducing the effects of sunglint. We also examine the impact of varying view and illumination geometry, changing the default bottom reflectance, and using a kernel processing scheme to normalize water properties over small areas. Results indicate robust model performance for most model formulations, with the most significant impact on model output being generated by differences in the atmospheric and deglint algorithms used for preprocessing.

Cs + ADC in rat brain decreases markedly at death.

Spectroscopic resolution of intracellular and extracellular compartments can be used to probe the kinetic environment of those spaces and the compartment-specific changes that occur following injury. This is important for understanding the biophysical mechanisms that underlie the remarkable diffusion-weighted MRI contrast of injured central nervous system (CNS) tissue. Cesium-133 is a physiologic analog of potassium that is actively taken up by cells and resides primarily in the intracellular space. The (133)Cs(+) signal can, thus, be exploited to probe the kinetic environment of the intracellular space. Two principal (133)Cs(+) resonances were observed at 11.74 T. These resonances arise separately from (133)Cs(+) in brain and temporalis muscle. The apparent diffusion coefficient (ADC) of Cs(+) in brain decreased from 1.0 +/- 0.2 microm(2)/ms in healthy tissue to 0.24 +/- 0.04 microm(2)/ms following global ischemia (average ADC +/- average uncertainty), while there was no significant change in the ADC of Cs(+) in temporalis muscle after injury. This finding underscores the tissue-specific nature of the decrease in ADC that accompanies brain injury. Further, as the Cs(+) ADC should reflect water ADC in the intracellular space, these results strongly support the hypothesis that the decrease in water ADC associated with CNS injury arises largely from kinetic changes taking place in the intracellular space.

Sodium ion apparent diffusion coefficient in living rat brain.

The apparent diffusion coefficient (ADC) of Na(+) was determined in live rat brain. The brain extracellular-to-intracellular Na(+) content ratio is approximately 8:2, which is the inverse of that for water in these spaces. Consequently, the ADC of Na(+) is primarily affected by motion in the extracellular space, and Na(+) can be viewed as a reporter molecule for motion in that space. Likewise, water ADC is dominated by intracellular motion. The brain Na(+) ADC was 1.15 +/- 0.09 microm(2)/ms, which is 61% of the aqueous Na(+) free diffusion coefficient (D(free)) at 37 degrees C (1.9 microm(2)/ms), while the ADC for brain water is 28% of the water D(free) at 37 degrees C (3 microm(2)/ms). This suggests that the ADC of molecular species within the extracellular space is roughly twofold that within the intracellular space. In postmortem brain, both Na(+) and water decrease to 17% of the respective D(free) values. These results are consistent with Na(+) and water ADC values sharing the same biophysical determinants in postmortem brain. The observed difference between Na(+) and water ADC/D(free) ratios in living brain tissue may be attributable to the extracellular environment hindering molecular displacements twofold less than the intracellular environment.