I have a different question: If Anavex has already proven efficacy in AD patients, why is this conference even being held?
For Anavex 2-73 to be used to benefit the maximum number of people, a lot of rethinking needs to be done by the Medical establishment.
A paper from Christoper Rowe, the first speaker:
For example, a number of neuropathological studies are reviewed in the study by Sweeney et al. with the contention that they demonstrate associations between AD and vascular disease. These studies, however, actually demonstrate that the Alzheimer's clinical syndrome is often associated with cerebrovascular pathology [4, 5]. In these studies, there is no evidence of any association between vascular disease and plaques and tangles. The individuals in these studies often suffered from a combination of AD and vascular diseases, but there was no evidence that greater vascular injury was associated with greater AD pathologic change. Thus, these cited studies do not show an association between cerebrovascular disease and AD, but rather between cerebrovascular disease and a clinical outcome that is fundamentally syndromic in nature. Other data support the interpretation that vascular risk factors exert their effects on cognition through pathways independent of plaque and tangle pathology [6].
Similarly, the authors cite imaging studies that have demonstrated reductions in cerebral blood flow, alterations in the blood-brain barrier (BBB), and the presence of vascular injury such as brain microbleeds in the brains of individuals diagnosed with “AD.” There are two crucial problems with the arguments raised. The first is again that these associations are not with any measure of AD pathologic changes. For example, cited studies showed an association between microbleeds and age or cognition [7, 8], with age and multiple different dementias (including the Alzheimer's clinical syndrome, vascular dementia, alcoholic dementia, and unspecified dementia) [9], and between microbleeds and structural connectivity in patients with the Alzheimer's clinical syndrome [10]. One study showed diminished cerebral blood flow in large and medium vessels in individuals at risk for AD [11]; however, this was a group of asymptomatic individuals with a high proportion of individuals with a family history of AD, but the only AD-related variable, apolipoprotein E (APOE) genotype, was unrelated to perfusion measures. In other words, these studies do not demonstrate an association between vascular factors and what we have termed AD, but rather between vascular factors and either an Alzheimer's clinical syndrome, or dementia, or other features even more remotely associated with dementia. Similarly, although evidence of BBB alterations in aging and cognitive impairment is an important potential link between blood-brain transport and AD pathologic changes [12, 13], this link remains unestablished. The second problem is that for modalities for which associations are better established, there is no evidence of causality. For example, perfusion reductions in the Alzheimer's clinical syndrome are widely reported, but these can also be interpreted as reflecting a phenomenon secondary to reduced tissue demand. Thus, the cited evidence is neither specific to AD pathologic changes nor is it linked to causal mechanisms underlying AD pathologic changes.
A key step in their argument involves a radical reinterpretation of FDG-PET data by proposing that reduced tracer uptake does not reflect hypometabolism but rather vascular dysfunction at the BBB. This is a radical notion if for no other reason than by this account virtually all brain disorders would reflect BBB dysfunction because virtually every neurological brain disorder and many psychiatric illnesses are associated with reductions in FDG-PET signal. There are more fundamental reasons to doubt this interpretation though. First, although it is true that FDG does not track the entire metabolic pathway of glucose metabolism, there is no requirement that a PET tracer behave identically to its tracked substrate; for example, neuroreceptor ligands do not have to trigger signal transduction, and dopamine tracers do not have to be metabolized to dopamine. FDG is, as the authors state, a substrate for hexokinase. Hexokinase is regulated by metabolic need, specifically by intracellular glucose-6-phosphate concentrations. As metabolism increases, glucose-6-phosphate concentrations decline, increasing hexokinase activity. This is perfectly captured by greater tissue trapping of FDG through its phosphorylation. FDG certainly does not capture every step in the metabolic production of ATP by either glycolysis or oxidative phosphorylation. However, its trapping based on hexokinase activity reflects metabolism. From a pharmacokinetic perspective, the Sweeney et al. interpretation is also incorrect. It is true that some dynamic PET studies have demonstrated evidence for reduced BBB transport of FDG. This is seen as a reduction in the fitted model parameter K1, which itself reflects the product of perfusion and extraction. Both perfusion and extraction decline in response to reduced metabolic demand. Thus, the cited PET studies do not necessarily reflect a primary abnormality at the BBB. More to the point, a number of these cited dynamic studies have also shown reductions in the model parameter k3, which reflects phosphorylation by hexokinase [14, 15, 16], consistent with a primary defect in metabolism. Finally, recent data obtained with magnetic resonance spectroscopy actually show that glucose is increased in the brain of individuals with the Alzheimer's clinical syndrome, indicating that vascular factors do not limit transport and likely reflect reduced tissue glucose consumption [17].
Sweeney et al. advocate using gadolinium (Gd)-based diffusion contrast imaging as a BBB integrity measure in AD research. First, we point out that (unlike amyloid or pathologic tau PET tracers for example) Gd accumulation in tissue implies no specific molecular affinity. Gd accumulates in any area of the brain where the BBB is disrupted and in any disease where this occurs (multiple sclerosis, tumor, etc.), and therefore this phenomenon bears no disease specificity. Accumulated Gd accelerates the natural relaxation rate of nearby water protons. More importantly, though, we urge caution on the part of AD researchers who might consider employing this approach. Gd contrast compounds may not be innocuous. In addition to the rare possibility of nephrogenic systemic fibrosis in patients with renal insufficiency, Gd appears to be retained in certain brain regions (e.g., cerebellar dentate) in people with intact BBBs. This is more likely with less-stable Gd chelates (macrocyclic are more-stable than linear compounds), and the clinical significance if any is unclear at this point. However, owing to the uncertainty of long-term safety, the FDA now requires notification of potential risks to all outpatients receiving Gd injections. FDA medication guides that include guidelines for various MR contrast agents can be found here: https://www.fda.gov/Drugs/DrugSafety/ucm085729.htm. Investigators considering adding Gd-based diffusion contrast imaging to their research protocol should be aware of this requirement.
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