Another try at alzheimer's cure?

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Another try at alzheimer's cure?

Postby vivian maxine on March 25th, 2017, 10:52 am 

The treatment of amyloids as a hope-for cure for alzheimer's was a failure. Now we have a new path to follow. Investigators at Rush University Hospital and Brigham and Women's Hospital have discovered a new gene that is associated with susceptibility to Tau pathology in the brain. PTPRD (Protein Tyrosine Phosphatase Receptor-type Delta) gene contributes to the Neurofibrillary tangle. It is hoped that a search for a drug to attack this variant gene will be more successful.

https://www.sciencedaily.com/releases/2 ... 144538.htm
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Re: Another try at alzheimer's cure?

Postby doogles on March 26th, 2017, 5:48 am 

This is another thread I find interesting vivian maxine.

It’s not that I’m interested so much in Alzheimers disease i(AD) itself, but I’m intrigued at the amount of research being conducted into the esoteric biochemical aspects of brain metabolism associated with the disease, when a mass of evidence suggests that readily available cheap vitamins are at hand, could be useful, but are being largely ignored.

This is a 2016 review of the literature on The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease by Grimm, Mett and Hartmann in the Int J Mol Sci (http://www.mdpi.com/1422-0067/17/11/1785/htm)

The full article is available free if anyone is interested.

I have taken the following excerpts out myself to make a point.

On vitamin A “Significantly-lowered serum and plasma concentrations of vitamin A and the provitamin A β-carotene have been observed in AD patients [36,37,38] and enhanced β-carotene plasma levels have been found to be associated with better cognitive performances in the elderly [39].” I would expect that when four studies produce such results that someone would have conducted a trial with sensible doses of vitamin A, but the authors of the review state – “However, so far there are no trials analyzing the impact of vitamin A supplementation on the progression of AD in humans.” Why?

On vitamin D“Several studies reported a reduced vitamin D3 concentration in the serum/plasma of patients suffering from all cause dementia and AD [33,57,58]. Additionally, low serum vitamin D3 levels were found to be associated with an enhanced risk of cognitive decline in general and in AD [59,60,61,62,63]. In contrast, elevated 25-(OH)D3 plasma/serum levels have been linked to increased cognitive function and greater volumetric measures of several brain structures typically affected by AD [64,65].” It appears that the only trial of vitamin D reported by these authors was in patients already receiving a proprietary preparation called “memantine”. “Annweiler et al. demonstrated the supplementation of vitamin D3 improved cognition and memory in patients with moderate AD receiving memantine [70]. This might be based on a synergistic neuroprotective effect of memantine plus vitamin D, as illustrated by the reduction of Aβ-induced axonal degeneration in the presence of these compounds [71]. The authors suggested the combination of memantine and vitamin D3 to represent a new multi-target therapeutic class for AD treatment [70,72].” Why hasn't vitamin D been trialled on its own?

On vitamin E “In the plasma of patients with AD and mild cognitive impairment (MCI), significantly lowered vitamin E levels have been found [36,37,89,90]. Inversely, higher plasma vitamin E concentrations and an enhanced dietary intake of vitamin E or α-tocopherol equivalents are associated with a reduced AD risk [91,92,93]. Recently, an association between an enhanced γ-tocopherol level and lowered AD neuropathology in human post mortem AD-brain tissue was reported, while α-tocopherol is associated with a higher Aβ load when γ-tocopherol levels are low [94].” As distinct from the other fat-soluble vitamins, there appear to have been trials conducted with vitamin E but with mixed results, and cautions about using too much. “Several studies analyzed the impact of vitamin E supplementation on AD progression leading to inconsistent results. While a reduction of the need for care and of disease progression for AD-patients treated with 2000 IU/day α-tocopherol was reported in some trials [95,96], other authors found vitamin E supplementation to have no beneficial effect, or to result in an even more rapid cognitive decline in patients with MCI or AD [97,98]. In this context it should be mentioned that high dosage vitamin E supplements might increase all-cause mortality, as reported by Miller et al., leading the authors to conclude that dosages of more than 400 IU vitamin E/day should be avoided [99].”

On vitamin K “In analogy to vitamins A, D, and E, the dietary intake of phylloquinone and, hence, the serum vitamin K concentration, is reported to be decreased in persons suffering from AD [145,146,147]. A possible role of vitamin K in AD-pathogenesis is further given by the discovery of a positive correlation between the serum vitamin K level and the cognitive functions of AD patients [147,148]. Additionally, the use of vitamin K antagonists as anticoagulant medications is associated with a more frequent cognitive impairment among geriatric patients [149].” Once again, although associations between dietary intakes and serum concentrations of phylloquinone with the prevalence of AD have been demonstrated in several studies, the authors of this review concluded – “However, so far there are no further data available regarding the impact of vitamin K on the pathological mechanisms of AD.” Why?

Maybe a cocktail of fat-soluble vitamins could even be trialled in an initial study. I realise the above review does not rule out fats themselves as maybe being useful, with the possibility that the vitamins may just be serving as biomarkers of fats.

I like to think I’m rational and open-minded, but I don’t understand why, in view of the findings in the above, and other, reviews, that fat-soluble vitamins (except for vitamin E) have not been trialled. They are readily available, cheap, easily administered, and I'm sure that ample voluntary subjects would put their hands up in retirement homes.

Is the source of research funding now limited to drug companies or university labs that rely on patents of new medications to survive?

I'm curious to hear any other ideas on this.
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Re: Another try at alzheimer's cure?

Postby vivian maxine on March 26th, 2017, 7:21 am 

Thank you, doogles, for the ideas. I'll check the link. You hit on my pet theory, also - chemicals. Some years ago it dawned on me that, of all the victims of alzheimer's I have known, only one was not loading herself with medicines over the years before ever going into alzheimer's. I have often wondered if these foreign-to-the-body chemicals contributed to the disease. I once wrote to an alzheimer's association and asked if this possibility was being researched. The answer was "no'. I suppose they know more than I about it but I think it worth a look.

I am not saying that medicine is not necessary at times. I am saying that too many people get onto them and never stop. Eventually, their list overwhelmingly long. Can the brain stand all of these chemicals?

Then, of course, there is "keep the mind active" which everyone knows about. So many ways to prevent so a pill never becomes necessary.

Just my thoughts.
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Re: Another try at alzheimer's cure?

Postby neuro on April 14th, 2017, 10:52 am 

You might be interested about a different line of research, which appears to imply a possible dopaminergic dysfunction in the pathogenesis of AD.

The idea is that insufficiency of the mesolimbic system, which originates in the ventral tegmental area and projects to the nucleus accumbens and hippocampus, would play a pathogenetic role in determining neuronal suffering in the cortex and hippocampus, thereby determining cognitive impairment in a way not exactly similar, but in some ways analogous, to the motor impairment produced - in Parkinson's disease - by the insufficiency of the dopaminergic system that projects to the dorsal striatum from the substantia nigra.

Interestingly enough, selegiline and l-DOPA, two drugs normally employed in Paarkinson's disease, have been shown to slow down AD course and prolong life in animal models and (though the numbers are still quite small) in humans as well.

A couple of refs:
Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease -- A. Nobili et al -- NATURE COMMUNICATIONS | 8:14727 | DOI: 10.1038/ncomms14727.

Front Aging Neurosci. 2015; 7: 67. -- Catecholamine-Based Treatment in AD Patients: Expectations and Delusions -- Alessandro Stefani et al.

Koch, G. et al. Altered dopamine modulation of LTD-like plasticity in Alzheimer’s disease patients. Clin. Neurophysiol. 122, 703–707 (2011).

Koch, G. et al. Dopaminergic modulation of cortical plasticity in Alzheimer’s disease patients. Neuropsychopharmacology 39, 2654–2661 (2014).

Monteverde, A., Gnemmi, P., Rossi, F., Monteverde, A. & Finali, G. C. Selegiline in the treatment of mild to moderate Alzheimer-type dementia. Clin. Ther. 12, 315–322 (1990).

Martorana, A. & Koch, G. Is dopamine involved in Alzheimer’s disease? Front. Aging Neurosci. 6, 252 (2014).
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Re: Another try at alzheimer's cure?

Postby vivian maxine on April 14th, 2017, 11:17 am 

Thank you, neuro. I almost said "wait until I get out my dictionary" but that goes without saying. I shall knuckle down to this.
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Re: Another try at alzheimer's cure?

Postby vivian maxine on April 14th, 2017, 4:14 pm 

In the first reference given in neuro's post, I found this: "We used TH immunostaining to identify DAergic neurons in Tg2576 and age-matched wild-type (WT) mice at different postnatal ages, and performed stereological cell counts in the VTA and SNpc of the midbrain (Fig. 1a). We observed a significant loss of DAergic neurons in Tg2576 mice, beginning at 3 months of age (Fig. 1b)."

I am sure I am misreading this. Maybe neuro or someone can straighten me out, please? Although it is not a "down-pat" age relationship, what I find says that a three-month old mouse is equivalent to a human age in the early 20s.

If this is accurate, would we be wrong to say we can predict who might develop alzheimer's later quite early in a human's life?
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Re: Another try at alzheimer's cure?

Postby neuro on April 18th, 2017, 6:26 am 

Well, Vivian,
this is exactly the question researchers are addressing.
Is it possible to spot early changes (cellular, biochemical, morphological markers) of neurodegenerative diseases?

The problem here is that experimental models of Alzheimer's disease do reproduce some features of the human pathology but cannot reproduce exactly its course and the precise pathogenesis.
Although some forms of Alzheimer's are related to well known genetic defects (APP, presenilins...), in most cases a single mutation is not sufficient to produce the disease, and the disease will anyway take several decades to manifest itself. Mice, on the contrary, live very few years: the pathogenic process is not likely to proceed in exactly the same way.

Still, recent imaging techniques promise to make us able to detect neurotransmitter deficiencies in specific regions of the CNS, and I would not exclude that in a reasonable time we shall be able to confirm whether a lack of dopamine in the VTA can be detected in healthy people and whether this is associated with an increased incidence of Alzheimer's disease, later on.
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Re: Another try at alzheimer's cure?

Postby vivian maxine on April 18th, 2017, 12:52 pm 

Thank you, neuro. That was pretty much my conclusion. Sometimes I fear what we are learning about the brain and what it does or controls. We need to learn it to get at the truth of it but that doesn't stop the fear of having that knowledge. Maybe it is the loss of what we formerly believed that brings this on - this knowing that we may not have been as in control as we thought we were. "Control" of how we will and will not act or react, I mean. There is a word that fits. I can't think of it.

On the other hand, if we can detect the flaws, perhaps we can do something about them. That's the bright side. Yes?
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Re: Another try at alzheimer's cure?

Postby neuro on April 22nd, 2017, 7:19 am 

vivian maxine » April 18th, 2017, 5:52 pm wrote:Maybe it is the loss of what we formerly believed that brings this on - this knowing that we may not have been as in control as we thought we were. "Control" of how we will and will not act or react, I mean. There is a word that fits. I can't think of it.

I apologize to everybody about saying this once more, but do you realize that this question of being (or not) in control arises from the unstated (but deeply felt) assumption that your brain is not you and you are not your brain?

It is as if, when we talk about these things, we were obliged to consider our brain as a spare part of our body, while WE are elsewhere... But nobody ever proved this to be true!
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Re: Another try at alzheimer's cure?

Postby vivian maxine on April 22nd, 2017, 9:01 am 

Neuro, did anyone ever prove it not to be true? I still feel it's a tad scary to know that a sphere of gray and white matter may be controlling what I think, say and do.

I rather like Michael Gazzaniga's "Who's in Charge?". Especially his final statement in his Afterward: "We are people, not brains. We are the abstraction that occurs when a mind, which emerges from a brain, interacts with the brain. It is in that abstraction that we exist and, in the face of science seeming to chip away at it, we are desperately seeking a vocabulary to describe what we truly are."

Mr Gazzaniga can talk like that. Me? there are too many angles to the story. It is more comfortable being certain.
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