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Is there any connection between autism/schizophrenia and dementia?
elainechem
Posted: Thursday, February 27, 2014 10:55 PM
Joined: 7/30/2013
Posts: 6037


I had been wondering whether having autism or schizophrenia increases or decreases the risk of  dementia. I've searched online, but could find no studies. 
Lane Simonian
Posted: Thursday, February 27, 2014 11:23 PM
Joined: 12/12/2011
Posts: 4998


They all have the same causative agent (peroxynitrites), but each has different features, so it is hard to say if one increases the risk for the other. For example, people with autism cannot easily breakdown polyphenols which may partially protect them from memory impairment caused by peroxynitrites in Alzheimer's disease.


Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease


Mark A. Smith,1 Peggy L. Richey Harris,1 Lawrence M. Sayre,2 Joseph S. Beckman,3 and George Perry1


http://www.jneurosci.org/content/17/8/2653.full.pdf


Targeting Peroxynitrite as a novel hypothesized treatment for autism spectrum disorders



elainechem
Posted: Friday, February 28, 2014 3:15 PM
Joined: 7/30/2013
Posts: 6037


Thanks Lane! I knew I could count on you. I suppose it depends on the type of dementia. My hubby has a diagnosis of VaD...and probably AD thrown in just for fun. But, since he had a mild form of autism, he might have some natural defense against AD.
Lane Simonian
Posted: Friday, February 28, 2014 10:48 PM
Joined: 12/12/2011
Posts: 4998


You are welcome, elainechem.  Yes, there is often a considerable overlap between vascular dementia and Alzheimer's disease.  And some overlap between autism and Alzheimer's disease: social withdrawal for instance.   


 

http://www.newautism.com/the-link-between-alzheimers-and-autism/836/ 


 

The inability to break down polyphenols can result in behavioral problems for people with autism, but except in more severe cases it is probably what limits the memory impairment in people with autism. 


 

http://scdlifestyle.com/2010/04/phenols-and-salicylates-what-they-are-and-why-it-matters/ 

 

http://www.hindawi.com/journals/omcl/2012/914273/


 

My best wishes to you and your husband.  I know that it is a tough journey, but progress is being made on the research front.  I only wish that it were faster. 


Lane Simonian
Posted: Wednesday, November 26, 2014 10:08 AM
Joined: 12/12/2011
Posts: 4998


A recent study suggested that schizophrenia and Alzheimer's disease affected the same part of the brain.  Both diseases are linked to the same receptor--the NMDA receptor and both may be triggered by oxidation.  But here is something interesting--schizophrenia is linked to NMDA receptor hypofunction (perhaps due to calcium deficiency) whereas Alzheimer's disease (and likely autism, too) is linked to NMDA receptor hyperfunction (due to nitration).  Both hyperfunction and hypofunction of NMDA receptors can contribute to memory loss and hallucinations.
Lane Simonian
Posted: Wednesday, November 26, 2014 4:54 PM
Joined: 12/12/2011
Posts: 4998


Here is a good article on the role of NMDA receptors in various neuropsychiatric disorders:


N-Methyl-D-aspartate (NMDA) receptors play a variety of physiologic roles and their proper signaling is essential for cellular homeostasis. Any disruption in this pathway, leading to either enhanced or decreased activity, may result in the manifestation of neuropsychiatric pathologies such as schizophrenia, mood disorders, substance induced psychosis, Huntington’s disease, Alzheimer’s disease, and neuropsychiatric systemic lupus erythematosus. Here, we explore the notion that the overlap in activity of at least one biochemical pathway, the NMDA receptor pathway, may be the link to understanding the overlap in psychotic symptoms between diseases. This review intends to present a broad overview of those neuropsychiatric disorders for which alternations in NMDA receptor activity is prominent thus suggesting that continued direction of pharmaceutical intervention to this pathway may present a viable option for managing symptoms.


http://journal.frontiersin.org/Journal/10.3389/fpsyt.2013.00052/full


The level of NMDA receptor activity varies between people with Alzheimer's disease and this may in part explain why some people with the disease have hallucinations and others do not.


Cannabinoids, eugenol, and ferulic acid all scavenge peroxynitrites and by doing so inhibit NMDA receptor activity.


http://www.pnas.org/content/95/14/8268.full


http://www.ncbi.nlm.nih.gov/pubmed/9147382


http://www.ncbi.nlm.nih.gov/pubmed/16257184


At certain levels of concentration or in combination with other antioxidants, they can have a positive effect on both cognition and behavior.  The problem with eugenol alone is that it can increase anxiety in some people, in part because it is associated with clove oil which was used in dental operations.  


http://www.ncbi.nlm.nih.gov/pubmed/9719038


Several clinical trials point to the use of various phenolic compounds (such as eugenol and ferulic acid) in the treatment of Alzheimer's disease.  




Lane Simonian
Posted: Wednesday, November 26, 2014 5:16 PM
Joined: 12/12/2011
Posts: 4998


And one for curcumin:


Excitotoxicity, mainly due to an overactivation of NMDA

receptors (NMDArs), has been proposed to be relevant in the

pathophysiology of CNS diseases, including ophthalmologic

disorders, such as retinal ischemia,14 diabetic retinopathy,15

and glaucoma.16,17 We previously reported the protective effect

of curcumin against NMDA-induced excitotoxicity in rat

retinal cultures, suggesting a mechanism involving modification

of NMDAr activity.


http://www.iovs.org/content/52/2/1070.full.pdf


The studies on curcumin and for ferulic acid show an improvement in behavior but not much affect on cognition in those with Alzheimer's disease. The latter is likely a result of impaired absorption either into the bloodstream (curcumin) or into the brain (ferulic acid).  With increased absorption or with additional compounds, curcumin and ferulic acid may also improve cognition as well as behavior.


Lane Simonian
Posted: Wednesday, November 26, 2014 9:02 PM
Joined: 12/12/2011
Posts: 4998


I rarely have epiphanies, but this is close. Peroxynitrites play a role in autism, schizophrenia, and Alzheimer's disease, but only in Alzheimer's disease is there no check on peroxynitrite production.  Calcium deficiency may limit peroxynitrite formation in schizophrenia and the inability of people with autism to break down polyphenols limits peroxynitrite formation in autism. Both, however, come at a cost: calcium deficiency leads to NMDA hypofunction which contributes to hallucinations in schizophrenia and the inability to breakdown polyphenols can contribute to behavioral problems in autism.  On the other hand, the inability to stop peroxynitrite formation in Alzheimer's disease leads to the loss of most memory.  The only way to stop the formation of peroxynitrites and the progression of Alzheimer's disease is to use specific external antioxidants. 


 

Happy Thanksgiving to all! 


Lane Simonian
Posted: Sunday, February 1, 2015 12:13 PM
Joined: 12/12/2011
Posts: 4998


This may be the way to look at the similarities and differences between schizophrenia and Alzheimer's disease with hallucinations:

NR [NMDA receptor]/Hypo as a Disease Mechanism

Before analyzing the correlations between NR/hypo and Alzheimer's disease, it should be noted that there has been some interest in NR/hypo as a disease process, but this interest has been focused upon schizophrenia and not Alzheimer's disease. These two diseases are so totally different, in their symptoms and manifestations, that various published suggestions that NR/hypo is involved in schizophrenia (e.g., Olney and Farber 1995) would be regarded, by most neurologists, as teaching away from possible involvement as a causative mechanism in Alzheimer's disease. This may be one of the reasons that (apparently) no other neurological researchers have noticed any correlations between NR/hypo and Alzheimer's disease.

The main hypothesis that has been embraced by the excitotoxicity school of thought (including the Applicants, until recently) is that neuronal degeneration in Alzheimer's disease results from an excitotoxic mechanism involving excessive activation (i.e., hyperactivation) of NMDA receptors; this condition is referred to herein as NR/hyper. This school originally proposed that an NR/hyper mechanism might be operative throughout all stages of Alzheimer's disease; this was their attempt to explain the neuronal degeneration occurring in all stages. In the late 1980's and early 1990's, a number of excitotoxicologists, including the Applicants, published review articles propounding this hypothesis (see, e.g., Henneberry et al 1989; Olney 1989; Albin and Greenemayre 1992; and Beal 1992).

Today, researchers in the excitotoxicity school have not abandoned this position, but they have encountered a problem with it, which they have not figured out how to resolve. The problem is that recent evidence documents that in the aging brain, the NR system is not in a hyperactive condition; rather, with advancing age it becomes hypoactive (i.e., less than normally active). If, as they originally proposed, the NR system in Alzheimer's disease were in a hyper condition, it would be appropriate to treat this condition with an NMDA antagonist drug to suppress NR and thereby correct the hyper condition. However, if the NR system in Alzheimer's disease is already in a hypo condition, treatment with an NMDA antagonist drug would not seem to make any sense, because there is not any NR/hyper condition to correct. Therefore, the excitotoxicology school can also be described as being at an impasse; they currently are not able to recommend an effective treatment approach for patients with Alzheimer's disease.

Very recently, the Applicants have made new discoveries that provide a solution to the above problem. Their recent findings have caused them to realize that NR/hyper is only a relevant mechanism to explain a certain limited pathological process that occurs very early in Alzheimer's disease, prior to the onset of outwardly detectable symptoms. They now realize that in this early period, the disease process is undergoing a transformation, in which the NR/hyper mechanism effectively "burns out" and destroys a number of NMDA receptors; this type of burnout damage leaves those damaged neural circuits in an NR/hypo condition, in which they can no longer adequately respond to normal levels of stimulation by glutamate. As described elsewhere, the damaged NR/hypo condition then becomes a disease mechanism capable of destroying certain target neurons in various regions of the brain.

Thus, the initial NR/hyper state undergoes a transformation into its exact opposite--an NR/hypo state. This apparently paradoxical opposite condition then becomes responsible for the widespread neurodegeneration that occurs in Alzheimer's disease.

Here is where I slightly disagree. In some people with Alzheimer's disease, the NMDA receptor remains in a hyperfunctioning state due in part to nitration by peroxynitrites. So NMDA receptor antagonists such as Namenda may be of some value. But in those with hallucinations in Alzheimer's disease, the NMDA receptor becomes hypoactive so that NMDA receptor antagonists such as Namenda may become counterproductive (for somewhat different reasons the same may be also true of essential oil high in eugenol).

Ferulic acid because it inhibits both NMDA receptor hyperactivity and hypoactivity is one of the best natural products to treat hallucinations in dementia.

2011 Jul;11(3):309-14. doi: 10.1111/j.1447-0594.2010.00687.x. Epub 2011 Jan 28.

Effect of ferulic acid and Angelica archangelica extract on behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.


Abstract

AIM:

The behavioral and psychological symptoms of dementia place a heavy burden on caregivers. Antipsychotic drugs, though used to reduce the symptoms, frequently decrease patients' activities of daily living and reduce their quality of life. Recently, it was suggested that ferulic acid is an effective treatment for behavioral and psychological symptoms. We have also reported several patients with dementia with Lewy bodies showing good responses to ferulic acid and Angelica archangelica extract (Feru-guard). The present study investigated the efficacy of Feru-guard in the treatment of behavioral and psychological symptoms in frontotemporal lobar degeneration and dementia with Lewy bodies.

METHODS:

We designed a prospective, open-label trial of daily Feru-guard (3.0 g/day) lasting 4 weeks in 20 patients with frontotemporal lobar degeneration or dementia with Lewy bodies. Behavioral and psychological symptoms of dementia were assessed at baseline and 4 weeks after the start of treatment, using the Neuropsychiatric Inventory. The Neuropsychiatric Inventory scores were analyzed using the Wilcoxon rank sum test.

RESULTS:

Treatment with Feru-guard led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data.

CONCLUSION:

Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.


Effects of ferulic acid and Angelica archangelica extract (Feruguard) in patients with Alzheimer's disease

Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan

Background: Feruguard is a health food supplement composed of ferulic acid extracted from rice bran and garden angelica obtained from Angelica archangelica. In recent years, Feruguard has been reported to be effective against the core symptoms and behavioral and psychological symptoms of dementia (BPSD) of Alzheimer disease (AD) and dementia with Lewy bodies (DLB). We conducted a prospective study to verify the efficacy of this supplement with respect to the BPSD, the results of which are reported here. Methods: The subjects consisted of 24 patients who had been definitively diagnosed with AD or DLB. Based on an observation period of 4 months, a crossover study was conducted in which 12 patients were assigned to group A and 12 patients were assigned to group B. Each patient in group A took two packets of Feruguard daily for the first two months. The patients in group B took the same for the latter two months. The assessment methods consisted of NPI-D scores combining neuropsychiatric inventory (NPI), which is an evaluation scale for BPSD, with an evaluation of distress of the caregiver, MMSE and ADAS as tests of cognitive functions, and GDS15 as a depression scale. These parameters were measured before and after taking Feruguard followed by an examination of their changes. Moreover, SPECT imaging were also performed, and a comparative study of changes in cerebral blood flow before and after administration was conducted using SPM8. Results: In the 12 patients of group A at completion of testing, mean NPI score was observed to have decreased significantly (P = 0.003) from 18.08 before administration to 10.58 after administration. In addition, distress scores also decreased significantly (P = 0.000) from 12.17 to 7.50, thus demonstrating the ameliorative effects of Feru-Guard on BPSD. There were no significant differences observed for MMSE, ADAS or GDS15 scores before and after administration. In the comparison of changes in cerebral blood flow, significant increases were observed in the right occipital lobe, and left cerebellar hemisphere as compared with before administration. Conclusions: This study verified the usefulness of Feruguard for BPSD. We intend to conduct additional studies on larger numbers of subjects in the future.



Lane Simonian
Posted: Tuesday, February 3, 2015 10:21 AM
Joined: 12/12/2011
Posts: 4998


People with autism have increased neural plasticity in large part due to high levels of polyphenols in their bodies (individuals with autism cannot breakdown polyphenols).

Hyperplasticity in Autism Spectrum Disorder confers protection from Alzheimer’s disease

Therefore, our results suggest that individuals with ASD might be relatively protected from age-related cognitive decline and the risk of dementia.

http://www.medical-hypotheses.com/article/S0306-9877(14)00236-9/abstract?cc=y

https://www.sciencenews.org/article/autism-may-carry-benefit-buffer-against-alzheimer%E2%80%99s

http://link.springer.com/article/10.1007/s11064-007-9494-7

On the other hand, people with autism (or autism spectrum disorder) also have low levels of glutathione which is sometimes referred to as the brain's master antioxidant.

In Alzheimer's disease levels of glutathione are also at very low levels, but this antioxidant deficit can partially be offset with polyphenols in a Mediterranean diet.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024594/

http://cumc.columbia.edu/dept/sergievsky/cnd/pdfs/Mediterraneandietandad.pdf

And here is the key to the whole disease: amyloid and tau tangles are the consequence of oxidation not the cause. You can have high levels of amyloid and tangles if the oxidative insults are high but not yet prolonged (children exposed to air pollution in Mexico City) or if there is some antioxidant protection against increasing peroxynitrite levels (polyphenols in individuals with autism spectrum disorder, hydrogen sulfide in people with Down syndrome, uric acid in people with gout and co-morbidities) and not have Alzheimer's disease. As the brain's glutathione levels are exhausted, some internal or external antixoxidant must take its place. The task is to find those antioxidants or combination of antioxidants that are the most effective. Do that and Alzheimer's disease can be at least partially reversed.





Serenoa
Posted: Tuesday, February 10, 2015 4:51 AM
Joined: 4/24/2012
Posts: 484


Lane you really need to write a book. The knowledge you have is impressive and you are not restrained by mainstream medical dogma.

As for the connections with these three diseases, I would not doubt that there are some. I believe from what evidence I have seen (and I'm sorry I don't have time to pull up the articles), that there are connections to insulin resistance and maybe low HDL cholesterol. But, yes, it's beneficial to think in terms of the connections between all these degenerative diseases, and not that everything is separate.

Lane Simonian
Posted: Tuesday, February 10, 2015 12:58 PM
Joined: 12/12/2011
Posts: 4998


Thanks very much, Serenoa. I am trying to figure out why peroxynitrite formation leads to different outcomes and manifestations in various disease. I just typed in searches for insulin resistance, low HDL, autism, and schizophrenia and several articles came up. Both insulin and HDL are activators of the phosphatiylinositol 3-kinasea/Akt pathway so that may be part of the link.

I am glad that Myriam and you are back. We were slowing down noticeably in your absences.

Serenoa
Posted: Tuesday, February 10, 2015 5:37 PM
Joined: 4/24/2012
Posts: 484


I agree, the evidence that the PI3K pathway is critical to cell survival and proper functioning is overwhelming, and anything that interferes with that pathway (like insulin resistance) is harmful and probably one of the primary steps leading to neuro-degeneration.

Lane, I have been devoting my time to implementing the potential beneficial treatments that we have discussed on this board. I may have found a way to work with residential assisted living facilities to put some of these therapies into place. If I am successful, perhaps my methods could be expanded. I feel the whole philosophy behind our mainstream health care, otherwise known as "disease care," is flawed. Feel free to email me if you want to discuss specifics.