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Vascular Brain Injury Greater Risk Factor Than Amyloid Plaques in Cognitive Aging
Posted: Tuesday, February 12, 2013 1:43 PM
Joined: 12/6/2011
Posts: 3326

(Source: ScienceDaily) - Vascular brain injury from conditions such as high blood pressure and stroke are greater risk factors for cognitive impairment among non-demented older people than is the deposition of the amyloid plaques in the brain that long have been implicated in conditions such as Alzheimer's disease, a study by researchers at the Alzheimer's Disease Research Center at UC Davis has found. The study found that vascular brain injury had by far the greatest influence across a range of cognitive domains, including higher-level thinking and the forgetfulness of mild cognitive decline.

The researchers also sought to determine whether there was a correlation between vascular brain injury and the deposition of beta amyloid plaques, thought to be an early and important marker of Alzheimer's disease, said Bruce Reed. "We looked at two questions," said Reed. "The first question was whether those two pathologies correlate to each other, and the simple answer is 'no.' Earlier research, conducted in animals, has suggested that having a stroke causes more beta amyloid deposition in the brain. If that were the case, people who had more vascular brain injury should have higher levels of beta amyloid. We found no evidence to support that."

"The second," Reed continued, "was whether higher levels of cerebrovascular disease or amyloid plaques have a greater impact on cognitive function in older, non-demented adults. Half of the study participants had abnormal levels of beta amyloid and half vascular brain injury, or infarcts. It was really very clear that the amyloid had very little effect, but the vascular brain injury had distinctly negative effects The more vascular brain injury the participants had, the worse their memory and the worse their executive function -- their ability to organize and problem solve," Reed said.

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Lane Simonian
Posted: Wednesday, February 13, 2013 1:59 PM
Joined: 12/12/2011
Posts: 5174

More evidence that amyloid plaques are not the main cause of Alzheimer's disease or other forms of dementia. 



The amyloid cascade hypothesis states that amyloid-beta accumulation is the key event in Alzheimer disease neurodegeneration. However, recent data put this model into question. Knopman DS et al (Ann. Neurol. recently compared cognitively normal elderly human subjects with amyloid-beta deposition (with or without neuronal injury) to individuals with neuronal injury but no amyloid-beta deposition.  The first group was classified as having preclinical Alzheimer’s Disease. The second group (lacking amyloid-beta deposition) was designated as having suspected non-Alzheimer pathology (SNAP).


However, in the SNAP group, 10% of subjects converted to mild cognitive impairment (MCI) or dementia within one year. This does not fit the classical amyloid cascade hypothesis stages of (1) amyloidosis first, then (2) presence of both biomarkers of neuronal injury and amyloid-beta, (3) and third, appearance of subtle cognitive impairment.


It was noted that the 10% conversion rate within a year (for the SNAP group) was not markedly different from that seen in the preclinical Alzheimer’s Disease group. The authors concluded that the initial appearance of brain-injury biomarkers in cognitively normal people may not depend on amyloid-beta amyloidosis. New views which replace the classical amyloid cascade hypothesis now suggest that amyloid-beta, tau and possibly other pathologies may be partly independent of each other. Examples include amyloid-beta-independent neuronal injury in apolipoprotein-E4 carriers. Further work is warranted.

Chételat G: Aβ-independent processes – rethinking preclinical AD. Nature Reviews Neurology [Epub ahead of print, February 12, 2013; doi:10.1038/nrneurol.2013.21] 


The likely path to Alzheimer's disease is found on the left side of this chart. 



 Phospholipase C activity leads to intracellular calcium release which leads to the formation of amyloid plaques (and to a certain degree via metals within the plaques to peroxynitrites--the main oxidant in Alzheimer's disease). 


Phospholipase C activation of Protein kinase C results in increased p38 MAPK activation which leads to peroxynitrites which likely causes Alzheimer's disease.  Ironically, Protein kinase C activity may actually slow down the production of amyloid plaques. 


So it is highly possible to see peroxynitrite-mediated neuronal damage before the presence of intracellular amyloid plaques.   


Following are some of the consequences of Protein kinase C activation in Alzheimer's and other diseases. 


The collaborative study found that protein kinase C (PKC), an enzyme located inside brain cells, may play a critical role in neuropsychiatric disorders, such as schizophrenia, Tourette syndrome, movement disorders and dementia.


The study showed that activation of protein kinase C impairs proper memory function in the brain's prefrontal cortex, the most evolved brain system responsible for attention span, perseverance, planning, judgment, impulse control, organization, self-monitoring and supervision, problem solving, critical and forward thinking, learning from experience and mistakes, ability to feel and express emotions, empathy and internal supervision. When protein kinase C is activated, the result is dramatically decreased performance of ordinary tasks.


Scientists now believe that hyperactivity of this enzyme contributes not only to sensations of stress but also to behavioral conditions such as schizophrenia, bipolar disorder and attention deficit hyperactivity disorder.


Researchers observed a reduction in memory-related cell activity among rat and monkey models under exposure to conditions of stress and increased levels of this particular enzyme. In this instance, the conditions were induced by chemicals. Heightened levels of norepinephrine, a neurotransmitter (a molecule that transmits signals from one nerve cell to another across the synapse), coupled with PKC, were detected under these circumstances. Symptoms ranged from distractibility and poor judgment to thought disorder and possible hallucination. 


Another implication of these studies is that amyloid plaques (particularly extracellular plaques) is not a very effective biomarker for the risk for Alzheimer's disease.  The best biomarker is myo-inositol (which in the above chart would be above PIP2--phosphatidylinositol 4,5 biphosphate).   



To explore the potential value of myo-inositol (mIns), which is regarded as a biomarker for early diagnosis of Alzheimer's disease, in APP/PS1 transgenic (tg) mice detected by (1)H-MRS.



Of the early AD metabolites as detected by (1)H-MRS, mIns is the most valuable marker for assessment of AD. Quantitative analysis of mIns may provide important clues for early diagnosis of AD.


High glucose levels, high blood pressure (due to high sodium levels), and Down syndrome all contribute to high levels of myo-inositol and all three are risk factors for Alzheimer's disease. 


Finally the current strategy to treat Alzheimer's disease is flawed.  Amyloid plaques are not the main cause of neuronal damage and removing them early will at the very best only slightly slow down the progression of the disease.  The FDA and pharmaceutical companies are going by the idea If at first you don't succeed, give the drug earlier.  They are doubling down with little prospect of success. 


We are almost there.  Almost. 


Lane Simonian
Posted: Thursday, February 14, 2013 10:11 AM
Joined: 12/12/2011
Posts: 5174

More bad news about immunotherapy against amyloid plaques to treat Alzheimer's disease. 



Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease. 


Aside from a reasonable safety profile, the first published Phase 2 study of a blood-derived antibody preparation to treat Alzheimer’s disease looks inconclusive at best. The six-month dose-finding trial of Octapharma AG’s intravenous immunoglobulin (IVIg) missed its primary endpoint, failing to change plasma Aβ. The IVIg product also showed no signs of cognitive or functional benefit. 


In some earlier studies, amyloid beta levels were lowered and the disease did not advance in four out of sixteen people.  The likely explanation for the latter is this. 


Besides effects on Aβ, some researchers believe the mixture of natural antibodies in IVIg may treat AD via other effects on innate immunity.


Whether immunotherapies remove plaques or not is likely to make little difference because amyloid plaques themselves are not toxic, metals within the plaques damage but do not kill neurons, and removing the metals does not stop the peroxynitrite-mediated killing of cells. 


Fe2+ alone transiently enhanced p38 MAPK and caspase-9 and -3 enzymes indicative for cell damage, but was not sufficient to cause cell death as previously indicated. GF, a PKC inhibitor or wortmannin, a blocker of the Akt pathway enhanced Aβ/Fe2+-induced toxicity, while SB, a p38 MAPK inhibitor, prevented cell damage and apoptosis. These findings further support the hypothesis that metal ion chelation and inhibitors of pro-apoptotic kinase cascades may be beneficial for Alzheimer's disease therapy. 


Metal chelators did not decrease peroxynitrite-mediated killing, indicating that exogenous transition metals were not required for toxicity. 


Many peroxynitrite scavengers are metal chelators and inhibit the pathways that lead to cell death via the formation of peroxynitrites.  The pharmaceutical companies have spent millions of dollars focusing on drugs that lower amyloid plaques levels and nothing on the study of peroxynitrites scavengers despite the fact that it has been long been known that peroxynitrite damage is widespread in Alzheimer's disease and that peroxynitrite scavengers have partially reversed Alzheimer's disease in either mice or "men."   My favorite quote on the treatment of Alzheimer's disease is this: 


[Clinical trials with over-the-counter supplements have concentrated either on
items which suppress inflammation, or on antioxidants which scavenge oxygen
derived free radicals. Most of these items have proved to be worthless in the
treatment of Alzheimer's disease. Similarly most drugs used to treat Alzheimer's
disease do little to slow the deterioration, but instead offer a mild temporary
symptom relief. However, evidence has been accumulating that the primary driver
of Alzheimer's disease is a nitrogen derived free radical called peroxynitrite,
which may mediate both amyloid and tau accumulation as well as their toxicity.
Excellent results have been obtained with peroxynitrite scavengers, with
reversals of Alzheimer's disease in human clinical trials being repeatedly
demonstrated. IMHO, the only thing which may be  preventing the abolition of
Alzheimer's disease is the mental inertia of scientists, as well as the
bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful
ones. Common sense is anything but...]