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Friday, September 21, 2012

The Hard Facts About bvFTD Nobody Wants To Tell You. Mortality And Progression.

The first question I had when I was diagnosed with bvFTD, (Well, right after, "What the Hell is that?"), was probably something like, "Well, Doc., how long do I have to live?" And then the doctor usually side-steps the question. They gave me some vague guesses, but really didn't answer the way I wanted. After all, plans need to be made!

Following are a couple studies that shed some light on the survival probabilities, or lack thereof. Remember that every case of bvFTD is different, and statistics do not predict individual outcomes. As a case in point, I was diagnosed a little over 2 and a half years ago, so I should be just about dead. Well, I am frakkin-well not dead yet, and not even considering it as an option! Screw'em!

It is interesting that there were 24 out of 91 phenocopy cases in the first study. This seems like a really high percentage to me. Not much is said about the criteria for diagnosis, or inclusion. The numbers are still dismal. The second study seems to do a slightly better job of addressing the non-progressive phenocopy cases of bvFTD, but the numbers are still dismal.
Title: Determinants of Survival in Behavioural Variant Frontotemporal Dementia.

Authors: Beatrice Garcin, Patricia Lillo, Michael Hornberger, Olivier Piguet, Kate Dawson, Peter Nestor, John Hodges

Journal: Neurology


Background: Behavior variant FTD (bvFTD) is a common cause of non-Alzheimer dementia. Little is known about its rate of progression but a recently identified subgroup seems to have an excellent prognosis (phenocopy cases) whereas the pathological cases decline rapidly. Data about natural history are needed to provide the best information to the patients and their families.

Methods: We estimated survival in a large group of bvFTD patients (n=91) and reviewed their demographic and clinical features to determine how they affect prognosis.

Results: Median survival in the whole group of 91 patients was 10.6 years from symptom onset, and 7.3 years from diagnosis. Log rank tests showed that being a female, having a positive family history, language impairment and motor symptoms at first assessment were associated with a significant shorter survival. The estimated hazard ratio indicated that younger age at onset, a higher score on MMSE and ACE were associated with longer survival. After the exclusion of 24 “phenocopy” cases, the analysis was repeated in a subgroup of 67 patients. In this latter group, median survival was 7.9 years from symptom onset and 4.0 years from diagnosis. The only factor associated with shorter survival was the presence of language impairment.

Conclusions: The prognosis of bvFTD is poorer when there are language features at presentation. This study also provides evidence for the existence of a benign subgroup of patients with clinical features of bvFTD.

...and an excerp from another study, this one targeted at Phenocopy bvFTD, which shows little or no progression:

Nonprogressive behavioural frontotemporal dementia: recent
developments and clinical implications of the ‘bvFTD phenocopy
Christopher M. Kippsa,b, John R. Hodgesc,d and Michael Hornbergerc,d
Wessex Neurological Centre, Southampton University
NHS Trust, bDepartment of Clinical Neurosciences,
University of Southampton, Southampton, UK,
Neuroscience Research Australia and dSchool of
Medicine, University of New South Wales, Sydney,
Correspondence to Dr Christopher Kipps, Consultant
Neurologist and Honorary Senior Clinical Lecturer,
Wessex Neurological Centre, Southampton University
NHS Trust, Southampton SO16 6YD, UK
E-mail: christopher.kipps@soton.ac.uk
Current Opinion in Neurology 2010, 23:628–632
Purpose of review
The clinical features of behavioural variant frontotemporal dementia (bvFTD) are well
established; however, recent work has identified patients fulfilling diagnostic criteria for
the disease who do not appear to progress clinically. This review describes means of
distinguishing this group at an early stage from patients who are likely to deteriorate.
Recent findings
Despite indistinguishable clinical profiles, studies in a cohort of bvFTD patients showed
a particularly good prognosis in a subgroup of predominantly male patients in whom
initial structural imaging was normal. This could not be explained by differences in
disease duration, and was confirmed by subsequent PET studies. Retrospective review
of clinical data in these groups verified that the current clinical diagnostic criteria are
both insensitive to true progressive bvFTD, particularly in the early stages, and also
poorly specific. In contrast, measures of activity of daily living performance, executive
function and tests of social cognition appear to have better discriminatory value for
patients who show clear clinical progression, with many individual diagnoses verified by
post mortem examination in this group.
It remains doubtful that the nonprogressive group have a neurodegenerative disease.
The implication for the current clinical diagnostic criteria and their proposed revision is

Moreover, a retrospective survival analysis of a bvFTD
cohort [5] showed that those patients with abnormal scans
were largely dead or institutionalized within 3 years, in
line with median survival time in pathologically proven
cases of bvFTD [7 ]. However, patients with scan ratings
in the control range had a significantly better disease
prognosis, with some patients surviving for 10 years or

So, the other question I had right away was something like, "How fast will this disease progress?" Once again the answer was unconvincing. They said that since my onset seemed to be rather slow, the progression should also be slow, so that maybe I had 10-12 years.

But how do you know if you have bvFTD if you are a fast or a slow progresser, or a phenotype case who may not even progress at all? That book I talked about, What If It's Not Alzheimer's?, gives some general guidelines that may be useful. I still highly recommend this book as I use it as a reference, and will repost the post about it if I can figure out how. It should also be available through a link on the sidebar of this blog somewhere - maybe lower left. It is worth the modest price.

According to the book,  losing 2 points per year, as in a declining test score on the MMSE (mini–mental state examination (MMSE) or Folstein test) is about average progression. Four points a year or more would indicate a rapid progression. If you lose 1 or no points you are a slow progresser, or even a phenocopy case. It may take several years to get a good idea of progression, and again: every case of bvFTD is different.

Comments are welcome.

Friday, September 14, 2012

TauRx Therapeutics LMTX® Phase 3 Clinical Trial Begins

..Ummm ...I think these are actually spleen cells, but they look like Pick's Bodies.
A special thanks to "Cherry Blossoms", a reader of this blog who recently posted a comment about this promising new drug and study.

The following is the  TauRx press release in its entirety.

Phase 3 Clinical Trial Begins in Early Form of Dementia

MANCHESTER, England, September 10, 2012 /PRNewswire/ --
Investigational drug study follows earlier study with promising results in mild to moderate Alzheimer's patients
TauRx Therapeutics today announced the initiation of a global Phase 3 clinical trial in a type of Frontotemporal Dementia (FTD) also known as Pick's Disease. The announcement, which immediately follows The 8th International Conference on Frontotemporal Dementias, held 5-7 September in Manchester, England, underscores the need for new treatments for this form of dementia that is similar to Alzheimer's Disease, except that it tends to damage different areas of the brain and affects people as early as 40 years old.
The study focuses on a type of FTD known as behavioural-variant, or bvFTD, which can cause early changes in personality and loss of empathy. A large percentage of these patients have a specific pathology that involves abnormal collections of tau protein in the brain.
The study drug, LMTX®, targets a process in the brain whereby a normal form of tau protein begins to self-aggregate due to binding neuronal waste-products. Once the process has started, the aggregates are able to propagate themselves indefinitely, using up normal tau protein and converting it into the toxic aggregates. After destroying the nerve cells where they are initially formed, the aggregates go on to infect nearby healthy neurons, progressively spreading and accelerating the destruction throughout the brain. LMTX® stops this aggregation process in its tracks and releases the trapped tau protein in a form which can be easily cleared by nerve cells.
In a pilot series of cases, LMTX® was found to arrest the progression of the disease. LMTX® has been found to act in a similar way on the aggregation of TDP-43 protein. Tau or TDP-43 aggregates each account for about 50% of patients with this early form of dementia.
Speaking to patients and caregivers at the FTD conference in Manchester, Professor Bradley Boeve of the Mayo Clinic in the U.S., one of the investigators of the study, said: "Clinicians devoted to FTD clinical trial development have been refining the measures to use in an experimental trial in FTD spectrum disorders for years, and frankly have been waiting for a promising agent. The basic science data for this agent, particularly in the tauopathies, looks sound and the excitement among investigators and among families is high."
The Phase 3 double-blind placebo-controlled study is designed to evaluate the safety and efficacy of LMTX®, the second-generation Tau Aggregation Inhibitor (TAI) developed by TauRx. The study aims to confirm the results first seen in the pilot cases in a larger controlled clinical trial in bvFTD patients over a 52-week timeframe. Participating study sites are located in Canada, U.S., U.K., Germany, The Netherlands, Australia and Singapore. Because the condition is relatively rare, TauRx was granted Orphan Designation for LMTX® in 2010, which provides a basis for more rapid approval for marketing if the trial is successful.
"This is an important step forward in our quest to find an effective treatment, with a goal to actually arrest the progression of the disease," said Professor Claude Wischik, founder and CEO of TauRx Therapeutics and Professor of Old Age Psychiatry at the University of Aberdeen. "We are building on over thirty years of research, and the encouraging results from our previous Phase 2 clinical trial in Alzheimer's Disease, which is also correlated with abnormal tau aggregates in the brain."
TauRx previously tested rember©, the first-generation TAI on which LMTX® is based, in a Phase 2 clinical trial involving 321 patients with mild and moderate Alzheimer's Disease in the UK and Singapore. This study found a 90% reduction in the rate of disease progression over two years in Alzheimer's Disease. Professor Wischik and his team have spent nearly 24 years investigating the structure and role of Tau tangles in the development of Alzheimer's disease, FTD and other neurodegenerative diseases. They were the original discoverers of the Tau protein pathology of Alzheimer's.
"It's very exciting news that a treatment is being tested for FTD in a clinical trial," said Penelope Roques of the Frontotemporal Dementia Support Group in the UK. "This is encouraging progress in a disease where there is currently no treatment available." The group has about 1,000 members across the UK, ranging from FTD patients, caregivers and family members.
If successful, this will be the first investigational drug that is able to arrest the progression of this disease. TauRx Therapeutics, a Singapore-based company spun out of the University of Aberdeen, developed the novel treatment based on an entirely new approach which targets aggregates of abnormal fibres of tau protein that form inside nerve cells in the brain. The TauRx team have since discovered that LMTX® could also have beneficial effects on other proteins which aggregate abnormally, including TDP-43 in FTD and synuclein in Parkinson's disease. In FTD, the frontal and temporal lobes are affected first, which impacts behaviour and emotion. As the disease progresses, other parts of the brain are affected, eventually producing a global dementia.
Patients and caregivers are invited to sign up for future updates as more news is available at http://www.PicksDementiaStudy.info.
About Pick's Disease:
According to the Association for Frontotemporal Degeneration (AFTD), bvFTD - or Pick's disease as it was originally known - can cause early and progressive changes in personality, emotional 'blunting' and loss of empathy. A person with the disorder may have difficulty controlling their behaviour, which can result in socially inappropriate responses or actions. Language may also be impaired after behavioural changes take place, as well as neurological symptoms such as movement and coordination difficulties. Over time, these symptoms worsen. The bvFTD form of the disease is particularly aggressive and progresses faster than Alzheimer's disease.
About TauRx:
TauRx Therapeutics was established in Singapore in 2002 with the aim of developing new treatments and diagnostics for a range of neurodegenerative diseases based on its technology platform. The TauRx team includes highly skilled and internationally recognised pharmaceutical experts in drug discovery and development. The company's Tau Aggregation Inhibitors (TAIs) include rember® and LMTX®, the second-generation drug that is being studied in Phase 3 clinical trials in Alzheimer's and FTD. TauRx is headquartered in Singapore with primary research facilities in Aberdeen, Scotland.
SOURCE TauRx Therapeutics

PR Newswire (http://s.tt/1mUod)

The effect of curcumin (turmeric) on Alzheimer's disease: An overview

This is the first a few research articles I found while following up on a comment left by a reader of this blog. It is not the most exciting reading, but it appears to very important information. Here it is without any editing.

The effect of curcumin (turmeric) on Alzheimer's disease: An overview

Ann Indian Acad Neurol. 2008 Jan-Mar; 11(1): 13–19.
doi:  10.4103/0972-2327.40220
PMCID: PMC2781139
The effect of curcumin (turmeric) on Alzheimer's disease: An overview
Shrikant Mishra and Kalpana Palanivelu
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
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This paper discusses the effects of curcumin on patients with Alzheimer's disease (AD). Curcumin (Turmeric), an ancient Indian herb used in curry powder, has been extensively studied in modern medicine and Indian systems of medicine for the treatment of various medical conditions, including cystic fibrosis, haemorrhoids, gastric ulcer, colon cancer, breast cancer, atherosclerosis, liver diseases and arthritis. It has been used in various types of treatments for dementia and traumatic brain injury. Curcumin also has a potential role in the prevention and treatment of AD. Curcumin as an antioxidant, anti-inflammatory and lipophilic action improves the cognitive functions in patients with AD. A growing body of evidence indicates that oxidative stress, free radicals, beta amyloid, cerebral deregulation caused by bio-metal toxicity and abnormal inflammatory reactions contribute to the key event in Alzheimer's disease pathology. Due to various effects of curcumin, such as decreased Beta-amyloid plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory, antioxidant and decreased microglia formation, the overall memory in patients with AD has improved. This paper reviews the various mechanisms of actions of curcumin in AD and pathology.
Keywords: Alternative approach to Alzheimer's, beta amyloid plaques, curcumin, curcumin and dementia, epidemiology, turmeric
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Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease. It is characterized by progressive cognitive deterioration together with declining activities of daily living and behavioral changes. It is the most common type of pre-senile and senile dementia. According to the World Health Organization (WHO), 5% of men and 6% of woman of above the age of 60 years are affected with Alzheimer's type dementia worldwide.[1] In India, the total prevalence of dementia per 1000 people is 33.6%, of which AD constitutes approximately 54% and vascular dementia constitutes approximately 39%. AD affects approximately 4.5 million people in the United States or approximately 10% of the population over the age of 65, and this number is projected to reach four times by 2050. The frequency increases to 50% by the age of 80 years. Every year more than $100 billion is spent for health care in the U.S. to treat AD in primary care settings alone.
Neuropathology of AD:

The neuropathological process consists of neuronal loss and atrophy, principally in the temporoparietal and frontal cortex, with an inflammatory response to the deposition of amyloid plaques and an abnormal cluster of protein fragments and tangled bundles of fibres (neurofibillary tangles). Neurotic plaques are relatively insoluble dense cores of 5-10 nm thick amyloid fibrils with a pallor staining “halo” surrounded by dystrophic neuritis, reactive astrocytes and activated microglia. There is an increased presence of monocytes/macrophages in the cerebral vessel wall and reactive or activated microglial cells in the adjacent parenchyma.[2,3] The main protein component of amyloid in AD is the 39-42 amino acid (beta) amyloid peptide (A-beta) [Figure 1].
Figure 1
Figure 1
Neuritic plaques are one of the characteristic structural abnormalities found in the brains of Alzheimer patients

Curcumin (Curcuma longa - Haldi) is the source of the spice Turmeric [Figure 2] and is used in curries and other spicy dishes from India, Asia and the Middle East. Similar to many other herbal remedies, people first used curcumin as a food and later discovered that it also had impressive medicinal qualities. It has been used extensively in Ayurveda (Indian system of Medicine) for centuries as a pain relieving, anti-inflammatory agent to relieve pain and inflammation in the skin and muscles. It has also proven to have anti-cancer properties.[4,5] Curcumin holds a high place in Ayurvedic medicine as a “cleanser of the body,” and today, science is finding a growing list of diseased conditions that can be healed by the active ingredients of turmeric.[6]
Figure 2
Figure 2
(2a) Turmeric, (2b) Turmeric plant, (2c) Keto and enol form of curcumin
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The Plant

Botanical name: Curcuma longa; Family: Zingiberaceae, the ginger family. Turmeric is a sterile plant and does not produce any seeds [Figure 2]. The plant grows up to 3-5 ft tall and has dull yellow flowers. The underground rhizomes or roots of the plant are used for medicinal and food preparation. The rhizome is an underground stem that is thick and fleshy ringed with the bases of old leaves. Rhizomes are boiled and then dried and ground to make the distinctive bright yellow spice, turmeric.
Turmeric History:

Probably originating from India, turmeric has been used in India for at least 2500 years. It is most common in southern Asia and particularly in India. Turmeric was probably cultivated at first as a dye and later on it was used as cosmetic and as an auspicious and aromatic food substance. It possesses antiseptic, anti-inflammatory detoxifying properties as well as carminative properties. Turmeric has a long history of medicinal use in South Asia and was widely used in Ayurvedic, Siddha and Unani systems. It is thought to be a hybrid selection and vegetative propagation of wild turmeric (Curcuma aromatica), which is native to India, Sri Lanka and the eastern Himalayas and some other closely related species.
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Curcumin and Alzheimer's Disease

Worldwide, there are over 1000 published animal and human studies, both in vivo and in vitro in which the effects of curcumin on various diseases have been examined. Studies include epidemiological, basic and clinical research on AD.
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Bio Chemical properties
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Epidemiological Studies

Various studies and research[9,10] results indicate a lower incidence and prevalence of AD in India. The prevalence of AD among adults aged 70-79 years in India is 4.4 times less than that of adults aged 70-79 years in the United States.[9] Researchers investigated the association between the curry consumption and cognitive level in 1010 Asians between 60 and 93 years of age. The study found that those who occasionally ate curry (less than once a month) and often (more than once a month) performed better on a standard test (MMSE) of cognitive function than those who ate curry never or rarely.[10]
Mechanism of action of curcumin on Alzheimer's disease:

The process through which AD degrades the nerve cells is believed to involve certain properties: inflammation, oxidative damage and most notably, the formation of beta-amyloid plaques, metal toxicity [Figure 3]. There have been several studies on effects of curcumin on AD. Outlined below are some of the studies and their conclusions.
Figure 3
Figure 3
Different mechanisms of action of curcumin in AD
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Effects of Curcumin on Macrophages

A study conducted at UCLA found that curcumin may help the macrophages to clear the amyloid plaques found in Alzheimer's disease. Macrophages play an important role in the immune system. They help the body to fight against foreign proteins and then effectively clear them. Curcumin was treated with macrophages in blood taken from nine volunteers: six AD patients and three healthy controls. Beta amyloid was then introduced. The AD patients, whose macrophages were treated with curcumin, when compared with patients whose macrophages were not treated with curcumin, showed an improved uptake and ingestion of the plaques. Thus, curcumin may support the immune system to clear the amyloid protein.[11]
Curcumin on glial cells:

Recent histological studies reveal the presence of activated microglia and reactive astrocytes around A-beta plaques in brains from patients with AD. The chronic activation of microglia secretes cytokines and some reactive substances that exacerbate A-beta pathology. So neuroglia is an important part in the pathogenesis of AD. Curcumin has a lipophilic property and can pass through all cell membranes and thus exerts its intracellular effects. Curcumin has anti-proliferative actions on microglia. A minimal dose of curcumin affects neuroglial proliferation and differentiation. Its inhibition of microglial proliferation and differentiation were studied and researched by the University of Southern California Los Angeles (UCLA). Researchers[12] using doses of 4, 5, 10, 15, 20 microM concentration of curcumin in C-6 rat glioma 2B-clone cells, a mixed colony of both neuroglial cells in a six- day trial, showed that curcumin dose dependently stops the proliferation of neuroglial cells, by differentiate into a mature cell or undergo apoptosis. It inhibits neuroglial cells proliferation dose dependently (i.e.) higher the concentration, the greater the inhibition. It has shown to decrease the glutamine synthetase (GS) assay, a marker enzyme for astrocytes. In the same study, curcumin was shown to increase CNP (2′3′- cyclic Nucleotide 3′-phosphohydrolase), a marker enzyme for oligodendrocytes. The overall effect of curcumin on neuroglial cells involves decreased astrocytes proliferation, improved myelogenesis and increased activity and differentiation of oligodendrocytes.
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Curcumin as an Anti Inflammatory in Alzheimer's

One of the important pathogenesis in Alzheimer's disease is the chronic inflammation of nerve cells. Several studies have demonstrated the associated inflammatory changes such as microgliosis, astrocytosis and the presence of pro-inflammatory substances that accompany the deposition of amyloid-β (Aβ) peptide. Patients with the prolonged use of certain nonsteroidal anti-inflammatory (NSAID) drugs such as ibuprofen have been shown to have a reduced risk of developing the symptoms of AD; however, the chronic use of NSAID can cause a toxic effect on the kidneys, liver and GI track. Curcumin has a potent anti-inflammatory effect. Through its various anti-inflammatory effects, it may have a role in the cure of AD. Curcumin inhibits Aβ-induced expression of Egr-1 protein and Egr-1 DNA-binding activity in THP-1 monocytic cells. Studies have shown the role of Egr-1 in amyloid peptide-induced cytochemokine gene expression in monocytes. By inhibition of Egr-1 DNA-binding activity by curcumin, it reduces the inflammation. The chemotaxis of monocytes, which can occur in response to chemokines from activated microglia and astrocytes in the brain, can be decreased by curcumin.[13,14]

Curcumin is found to inhibit cyclooxygenase (COX-2), phospholipases, transcription factor and enzymes involved in metabolizing the membrane phospholipids into prostaglandins. The reduction of the release of ROS by stimulated neutrophils, inhibition of AP-1 and NF-Kappa B inhibit the activation of the pro-inflammatory cytokines TNF (tumor necrosis factor)-alpha and IL (interleukin)-1 beta.[15,16] Overall, curcumin decreases the main chemical for inflammation and the transcription of inflammatory cytokines. Curcumin inhibits intracellular IL-12 p40/p70 and IL-12 p70 expression. The exposure to curcumin also impaired the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF-). These studies indicate a potent inhibitor of pro-inflammatory cytokine production by curcumin and it may differ according to the nature of the target cells.
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Curcumin as an Anti-oxidant

Curcumin inhibits the activity of AP-1, a transcription factor involved in expression of amyloid, which is linked to AD. Curcuminoids are proven to have strong antioxidant action demonstrated by the inhibition of the formation and propagation of free radicals. It decreases the low-density lipoprotein oxidation and the free radicals that cause the deterioration of neurons, not only in AD but also in other neuron degenerative disorders such as Huntington's and Parkinson's disease.[16] In one study, curcuma oil (500 mg Kg(-1) i.p.) was given 15 min before 2 h middle cerebral artery occlusion, followed by 24 h reflow in rats. This significantly diminished the infarct volume, improved neurological deficit and counteracted oxidative stress.[17]

A study conducted at Nanjing Medical University (China) showed that a single injection of curcumin (1 and 2 mg/kg, i.v.) after focal cerebral ischemia/reperfusion in rats significantly diminished the infarct volume, improved neurological deficit, decreased mortality and reduced the water content in the brain.[18]

Curcumin has powerful antioxidant and anti-inflammatory properties; according to the scientists, these properties believe help ease Alzheimer's symptoms caused by oxidation and inflammation.[19] A study conducted at Jawaharlal Nehru University (India) demonstrated that the administration of curcumin significantly reduced lipid peroxidation and lipofuscin accumulation that is normally increased with aging.[20] It also increased the activity of superoxide dismutase, sodium-potassium ATPase that normally decreased with aging. In another study, curcumin has been shown to protect the cells from betaA (1-42) insult through antioxidant pathway.[21] Curcumin protects brain mitochondria against various oxidative stress. Pre-treatment with curcumin protects brain mitochondria against peroxynitrite (a product of the reaction of nitric oxide with superoxide) a potent and versatile oxidant that can attack a wide range of cells in vitro by direct detoxification and in vivo by the elevation of total cellular glutathione levels.[22]
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Curcumin on Haemoxygenase Pathway

Natural antioxidant curcumin has been identified as a potent inducer of hemoxygenase, a protein that provides efficient cytoprotection against various forms of oxidative stress. By promoting the inactivation of Nrf2-keap1 complex and increased binding to no-1ARE, curcumin induces hemoxygenase activity. The incubation of astrocytes with curcumin at a concentration that promoted hemoxygenase activity resulted in an early increase in reduced glutathione, followed by a significant elevation in oxidized glutathione content.[23–25] Glutathione is an important water-phase antioxidant and essential cofactor for antioxidant enzymes protecting the mitochondria against endogenous oxygen radicals. Its level reflects the free radical scavenging capacity of the body. GSH depletion leads to tissue damage due to lipid peroxidation and oxidative damage.
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Beta-Amyloid Plaques

The most prominent characteristic feature in AD is the presence of beta-amyloid plaques. These plaques are basically an accumulation of small fibers called beta amyloid fibrils. Because the deposition of beta-amyloid protein is a consistent pathological hallmark of brains affected by AD, the inhibition of A-beta generation, prevention of A-beta fibril formation, destabilization of pre-formed A-beta would be an attractive therapeutic strategy for the treatment of AD. The levels of beta-amyloid in AD mice that were given low doses of curcumin were decreased by around 40% in comparison to those that were not treated with curcumin. In addition, low doses of curcumin also caused a 43% decrease in the so-called “plaque burden” that these beta-amyloid have on the brains of AD mice. Surprisingly low doses of curcumin given over longer period were actually more effective than high doses in combating the neurodegenerative process of AD.[26] At higher concentration, curcumin binds to amyloid beta and blocks its self assembly. The key chemical features in amyloid beta are the presence of two aromatic end groups and any alterations in these groups has profound effect on its activity.

Because of the lipophilic nature of curcumin, it crosses the blood brain barrier and binds to plaques. Curcumin was a better A-beta 40 aggregation inhibitor and it destabilizes the A-beta polymer. In in vitro studies, curcumin inhibits aggregation as well as disaggregates to form fibrillar A-beta 40. A Japanese study showed that using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, curcumin destabilizes the fA-beta(1-40) and fA-beta(1-42) as well as their extension.[27] Curcumin-derived isoxazoles and pyrazoles bind to the amyloid beta peptide (Abeta) and inhibit amyloid precursor protein (APP) metabolism.[28] Curcumin given to APPswe/PS1dE9 mice for 7 days crosses the blood-brain barrier as demonstrated by muliti-photon microscopy and reduces the existing senile plaques.[29] In another study, curcumin has been shown to increase the phagocytosis of amyloid-beta, effectively clearing them from the brains of patients with AD.[30]
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Metal Chelation

Studies showed that metals can induce A-beta aggregation and toxicity and are concentrated on Alzheimer's brain. Chelators' desferroxamine and cliquinol have exhibited anti-Alzheimer's effects. A study at Capital University Beijing demonstrated the toxicity of copper on neurons. A greater amount of H2O2 was released when copper (2)-A(beta)-40 complexes were added to the xanthene oxidase system. Copper was bound to A(beta)1-40 and was observed by electron paramagnetic resonance spectroscopy. In addition, copper chelators could cause a structural transition of A(beta). There was an increase on beta sheet as well as alpha-helix when copper was introduced.[31] Another study reveals that copper and zinc bind A-beta inducing aggregation and give rise to reactive oxygen species. There was a conformational change from beta sheet to alpha helix followed by peptide oligomerization and membrane penetration, when copper (or) zinc is added to A-beta in a negatively charged lipid environment.[32] Brain iron deregulation and its association with amyloid precursor protein plaque formation are implicated in the pathology of AD.[33]

Curcumin, by interaction with heavy metals such as cadmium and lead, prevents neurotoxicity caused by these metals. The intraperitoneal injection of lead acetate in rats in the presence of curcumin was studied microscopically. The results show lead-induced damage to neurons was significantly reduced in rats injected with curcumin.[34] A study at Chinese University of Hong Kong showed that by using spectrophotometry, the curcumin effectively binds to copper, zinc and iron. In addition, curcumin binds more effectively with redox-active metals such as iron and copper than the redox-inactive zinc. It is suggested that curcumin suppresses inflammatory damage by preventing metal induction of NF-kappa.[35,36]
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Cholesterol Lowering Effect

High-fat diets and increased blood cholesterol are linked to increased amyloid plaques by the intracellular accumulation of cholestryl esters.[37] Researchers believe that by inhibiting cholesterol formation and decreasing serum peroxides, curcumin might exert beneficial effects on AD.[38]
Oral bioavailability:

Curcumin has poor bioavailability. Because curcumin readily conjugated in the intestine and liver to form curcumin glucuronides.[39] In a clinical trial conducted in Taiwan, serum curcumin concentrations peaked one to two hours after an oral dose. Peak serum concentrations were 0.5, 0.6 and 1.8 micromoles/L at doses of 4, 6 and 8 g/day respectively.[40] It is also measured in urine at a dose of 3.6 g/day. Absorption is poor following ingestion in mice and rats. 38% to 75% of an ingested dose of curcumin is excreted in the feces. Absorption appears to be better with food. Curcumin crosses the blood brain barrier and is detected in CSF.
Side Effect

No apparent side effects have been reported thus far. GI upset, chest tightness, skin rashes, swollen skin are said to occur with high dose. A few cases of allergic contact dermatitis from curcumin have been reported.[41]

The chronic use of curcumin can cause liver toxicity. For this reason, turmeric products should probably be avoided by individuals with liver disease, heavy drinkers and those who take prescription medications that are metabolized by liver. Curcumin was found to be pharmacologically safe in human clinical trials with doses up to 10 g/day. A phase 1 human trial with 25 subjects using up to 8000 mg of curcumin per day for three months found no toxicity from curcumin.[42]

Curcumin is said to interact with certain drugs such as blood thinning agents, NSAIDs, reserpin. Co-supplementation with 20 mg of piperine (extracted from black pepper) significantly increase the bioavailablity of curcumin by 2000%.[43]

Curcumin is not recommended for persons with biliary tract obstruction because it stimulates bile secretion. It is also not recommended for people with gallstones, obstructive jaundice and acute biliary colic. Curcumin supplementation of 20-40 mg have been reported to increase gallbladder contractions in healthy people.[44,45]
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Epidemiological studies have shown that prevalence of AD is 4.4 lower amongst Indian Asians as compared to people of western origin.[9] D ementia incidence in western countries (P < 0.21) and East Asian countries were lower than that of Europe (P < 0.0004).[49]
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Experimental studies: Statistical significance

Clinical -Vivo: Blood from six patients with AD and three healthy controls was taken and the macrophage cells were isolated. After treatment of macrophages with curcuminoids, Aβ uptake by macrophages of three of the six AD patients was found to have significantly increased (P < 0.001 to 0.081).[11]

Five animal and two human studies showed statistically significant P values.
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Based on the main findings detailed above, curcumin will lead to a promising treatment for Alzheimer's disease. The clinically studied chemical properties of curcumin and its various effects on AD shows the possibility to do further research and develop better drugs based on curcumin for treating AD. The recent review paper of John Ringman also supports some of the abovementioned properties of curcumin in AD;[50] however, large-scale human studies are required to identify the prophylactic and therapeutic effect of curcumin.

Several unanswered questions remain: What is the one main chemical property of curcumin that can be exploited in treating AD? What is the role of curcumin in other neurological disorders such as Parkinson's, Huntington's and other dementias? How does curcumin interact with neuronal plaques? Is it effective only as a food additive? Would it be effective when used alone or with other anti inflammatory drugs?
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Source of Support: Nil

Conflict of Interest: Nil
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1. Fratiglioni L, De Ronchi D, Agüero-Torres H. Worldwide prevalence and incidence of dementia. Drugs Aging. 1999;15:365–75. [PubMed]
2. Bamberger ME, Landreth GE. Inflammation, apoptosis and Alzheimer's disease. Neuroscientist. 2002;8:276–83. [PubMed]
3. Di Patre PL, Read SL, Cummings JL, Tomiyasu U, Vartavarian LM, Secor DL, et al. Progression of clinical deterioration and pathological changes in patients with Alzheimers Disease evaluated at biopsy and autopsy. Arch Neurol. 1999;56:1254–61. [PubMed]
4. Shishodia S, Sethi G, Aggarwal BB. Getting back to roots. Ann NY Acad Sci. 2005;1056:206–17. [PubMed]
5. Ammon HP, Wahl MA. Pharmacology of curcuma longa. Planta Med. 1991;57:1–7. [PubMed]
6. Youssef KM, El-Sherbeny MA. Synthesis and antitumor activity of some curcumin analogs. Arch Pharm (Weinheim) 2005;338:181–9. [PubMed]
7. Kolev TM, Velcheva EA, Stamboliyska BA, Spiteller M. DFT and experimental studies of the structure and vibrational spectra of curcumin. Int J Quantum Chem. 2005;102:1069–79.
8. Payton F, Sandusky P. Alworth NMR study of the solution structure of curcumin WL PMID: 17315954(Pub Med)
9. Pandav R, Belle SH, DeKosky ST. Apolipoprotein E polymorphism and Alzheimer's disease: The Indo-US cross-national dementia study. Arch Neurol. 2000;57:824–30. [PubMed]
10. Ng TP, Chiam PC, Lee T, Chua HC, Lim L, Kua EH. Curry consumption and cognitive function in the elderly. Am J Epidemiol. 2006;164:898–906. [PubMed]
11. Zhang L, Fiala M, Cashman J, Sayre J, Espinosa A, Mahanian M, et al. Curcuminoids enhance amyloid -beta uptake by macrophages of Alzheimer's disease patients. J Alzheimers Dis. 2006;10:1–7. [PubMed]
12. Ambegaokar SS, Wu L, Alamshahi K, Lau J, Jazayeri L, Chan S, et al. Curcumin inhibits dose-dependently and time-dependently neuroglial proliferation and growth. Neuro Endocrinol Lett. 2003;24:469–73. [PubMed]
13. Giri RK, Rajagopal V, Kalra VK. Curcumin, the active constituent of turmeric, inhibits amyloid peptide-induced cytochemokine gene expression and CCR5-mediated chemotaxis of THP-1 monocytes by modulating early growth response-1 transcription factor. J Neurochem. 2004;91:1199–210. [PubMed]
14. Pendurthi UR, Rao LV. Suppression of transcription factor Egr-1 by curcumin. Thromb Res. 2000;97:179–89. [PubMed]
15. Park SY, Kim DS. Discovery of natural products from Curcuma longa that protect cells from beta-amyloid insult: A drug discovery effort against Alzheimers disease. J Nat Prod. 2002;65:1227–31. [PubMed]
16. Kim GY, Kim KH, Lee SH, Yoon MS, Lee HJ, Moon DO. Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-B as potential targets. J Immunol. 2005;174:8116–24. [PubMed]
17. Rathore P, Dohare P, Varma S, Ray A, Sharma U, Jaganathanan NR, et al. Curcuma oil: Reduces early accumulation of oxidative product and is anti-apoptogenic in transient focal ischemia in rat brain. Neurochem Res. 2007 Oct 23;
18. Jiang J, Wang W, Sun YJ, Hu M, Li F, Zhu DY. Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood-brain barrier damage. Eur J Pharmacol. 2007;30:54–62.
19. Frautschy SA, Hu W. Phenolic anti inflammatory antioxidant reversal of b induced cognitive deficits and neuropathology. Neurobiol Aging. 2001;22:993–1005. [PubMed]
20. Bala K, Tripathy BC, Sharma D. Neuroprotective and anti-ageing effects of curcumin in aged rat brain regions. Biogerontology. 2006;7:81–9. [PubMed]
21. Kim DS, Park SY, Kim JK. Curcuminoids from Curcuma longa L. (Zingiberaceae) that protect PC rat pheochromocytoma and normal human umbilical vein endothelial cells from betaA(1-42) insult. Neurosci Lett. 2001;303:57–61. [PubMed]
22. Mythri RB, Jagatha B, Pradhan N, Andersen J, Bharath MM. Mitochondrial complex I inhibition in Parkinsons disease: How can curcumin protect mitochondria? Antioxid Redox Signal. 2007;9:399–408. [PubMed]
23. Scapagnini G, Foresti R, Calabrese V, Giuffrida Stella AM, Green CJ, Motterlini R. Caffeic acid, phenethyl ester and curcumin: A novel class of heme oxygenase 1 inducer. Mol Pharmacol. 2002;61:554–61. [PubMed]
24. Jeong GS, Pal HO, Jeong SO, Kim YL, Shin MK, Seo BY, et al. Comparative effects of curcuminoids on endothelial heme oxygenase-1 expression: Ortho-methoxy groups are essential to enhance heme oxygenase activity and protection. Exp Mol Med. 2006;38:393–400. [PubMed]
25. Calabrese V, Butterfield DA, Stella AM. Nutritional antioxidants and the heme oxygenase pathway of stress tolerance: Novel targets for neuroprotection in Alzheimer's disease. Ital J Biochem. 2003;52:177–81. [PubMed]
26. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005;280:5892–901. [PubMed]
27. Ono K, Hasegawa K, Naiki H, Yamada MJ. Curcumin has potent anti-amyloidogenic effects for Alzheimer's beta fibrils in vitro. Neurosci Res. 2004;75:742–50.
28. Narlawar R, Pickhardt M, Leuchtenberger S, Baumann K, Krause S, Dyrks T, et al. Curcumin-derived pyrazoles and isoxazoles: Swiss army knives or blunt tools for Alzheimers disease? Chem Med Chem. 2008;3:165–72. [PubMed]
29. Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ. Curcumin labels amyloid pathology in vivo, disrupts existing plaques and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem. 2007;102:1095–104. [PubMed]
30. Fiala M, Liu PT, Espinosa-Jeffrey A, Rosenthal MJ, Bernard G, Ringman JM, et al. Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimers disease patients are improved by bisdemethoxycurcumin. Proc Natl Acad Sci USA. 2007;104:12849–54. [PMC free article] [PubMed]
31. Perry G, Sayre LM, Atwood CS, Castellani RJ, Cash AD, Rottkamp CA, et al. The role of iron and copper in the aetiology of neurodegenerative disorders. CNS Drugs. 2002;16:339–52. [PubMed]
32. DAI, Xueling, SUN, Yaxuan, JIANG Zhaofeng Copper (2) potentiation of Alzheimers A-(beta)1-40 cytotoxicity and transition on its secondary structure. Acta Biochimica et Biophysica Sinica. 1938;11:765–72.
33. Liu G, Huang W, Moir RD, Vanderburg CR, Barry AI, Zicheng P, et al. Metal exposure and Alzheimers pathogenesis. J Structural Biol. 2005;155:45–51.
34. Daniel S, Limson JL, Dairam A, Watkins GM, Daya S. Through metal binding, curcumin protects against lead- and cadmium-induced lipid peroxidation in rat brain homogenates and against lead-induced tissue damage in rat brain. J Inorg Biochem. 2004;98:266–75. [PubMed]
35. Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. Alzheimer's Dis. 2004;6:367–77.
36. Shukla PK, Khanna VK, Khan MY, Srimal RC. Protective effect of curcumin against lead neurotoxicity in rat. Hum Exp Toxicol. 2003;22:653–8. [PubMed]
37. Puglielli L, Tanzi RE, Kovacs DM. Alzheimer's disease: The cholesterol connection. Nat Neurosci. 2003;6:345–51. [PubMed]
38. Soni KB, Kuttan R. Effect of oral curcumin administration on serum peroxides and cholesterol in human volunteers. Indian J Physiol Pharmacol. 1992;36:273–5. [PubMed]
39. Ireson CR, Jones DJ, Orr Sl. Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol Biomarkers Prev. 2002;11:105–11. [PubMed]
40. Cheng AL, Hsu CH, Lin JK. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001;21:2895–900. [PubMed]
41. Liddle M, Hull C, Liu C. Powell D Contact urticaria from curcumin. Dermatitis. 2006;17:196–7. [PubMed]
42. Chainani N. Safety and anti-inflammatory activity of Curcumin component of turmeric (curcuma longa) J Alter Compl Med. 2003;9:161–8.
43. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998;64:353–6. [PubMed]
44. Rasyid A, Lelo A. The effect of curcumin and placebo on human gall-bladder function: An ultrasound study. Aliment Pharmacol Ther. 1999;13:245–9. [PubMed]
45. Rasyid A, Rahman AR, Jaalam K, Lelo A. Effect of different curcumin dosages on human gall bladder. Asia Pac J Clin Nutr. 2002;11:314–8. [PubMed]
46. Lim GP, Chu T, Yang F, Beech W, Frautschy SA. Cole GM The curry spice curcumin reduces oxidative damage and amyloid pathogenesis on Alzheimer's transgenic mouse. J Neurosci. 2001;21:8370–7. [PubMed]
47. Wu A, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity and cognition. Exp Neurol. 2006;197:309–17. [PubMed]
48. Suri AA. The anti-oxidative effects of curcumin on memory curves of planaria: A model for the treatment of Alzheimer's disease. 2003. p. S1425. Available from: http://www.usc.edu.
49. Jorm AF, Jolley D. The incidence of dementia: A meta analysis. Neurology. 1998;51:728–33. [PubMed]
50. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL. A potential role of the curry spice curcumin in Alzheimer's disease. Curr Alzheimer Res. 2005;2:131–6. [PMC free article] [PubMed]

Friday, September 7, 2012

Can a bvFTD Symptom be an asset? An anecdote.

If you are offended by some raw language now and then, now would be a good time to go read something else. I have bvFTD so foul language comes naturally to me on occasion, but most of the time I don't use foul language in my posts, but every now and then... well every now and then I just have to call an asshole what he is!

...and this little bastard garden-raider is next. You lookin at me?
I mentioned in an earlier post that my friend and I had several booth spaces at the local Corn Festival. Sales were good, and our booths were busy most of the time. It was a long and tiring day, but it was worth it. We had fun, and I enjoyed talking to people. Who knew I could sell aprons, purses, and tote bags?

My bvFTD was in the background most of the time. My friend and I actually spoke of this afterwards, and she said that when she noticed I was doing something, and got distracted, she gently guided me back on-track. She is good at it because I wasn't even aware she was doing it.

Sales work is a natural for someone with bvFTD (if they could actually ever do it and not just think about it and not yell at their boss or scream at their customers and get to work regularly and ... and ... but you know what I mean). One of the symptoms of bvFTD is a lack of self restraint. I am not shy about talking with anyone. I do not think it is possible to intimidate me. When I am not being a hermit, and locking myself up behind closed doors away from everyone, I am downright sociable!

Well, she turned me loose on the local population with good solid high quality products to sell, 20 years of marketing experience, a Master's Degree in Business, and bvFTD. They didn't stand a chance! We all had fun.

and then...

I kinda had a symptom, but it worked out for the best, and I can rationalize it all over the place, but at the end of the day it was a direct result of my bvFTD, and a symptom. I just gotta warn all of the other total assholes out there that the person you are dealing with just might have bvFTD and will not put up with any of your crap.

So, here is what happened. We had a slow period mid-afternoon, and Cindy went for a walk. She needed a break, and I encouraged her to go check out the other vendors and stuff at the festival. She is a hard worker. While she was gone I made a few sales. Then things got really slow in the booths.

I noticed a man standing right in front of our booth spaces with his back to me. He had several small children lined up on either side of him effectively forming a wall blocking access to our booth. No big deal. I figured maybe he was just waiting for someone ...until ...a customer came up to our booth to look at something and he blew smoke in her face. She promptly left the vicinity in a huff. To me this was a potential sale, and from what she was interested in it meant about $25 or so. I was suddenly more interested in this gentleman. Did I mention that I have bvFTD?

I walked right up to him, and before I could even ask him if I could help him with something, he turned to me, blew some smoke at me, and said kind of menacingly, "You got a problem?" I think he maybe was some kind of small-town hick bully used to intimidating people. He had no idea! Did I mention I have bvFTD? I can get really pissed-off for no reason in less than zero-point-seven-six seconds, and this bozo had just given me a reason. I was seething!

But, I am also very aware of my bvFTD symptoms sometimes, or at least I try to convince myself that I have some insight into my feelings in spite of my condition. So with great restraint I smiled at him, and asked If I could help him with something.

And then he said, being as rude as he possibly could, "Can't you see I had my back turned to you. If I wanted any help ...mumble ...mumble..." as he turned away.

Well, I did not grab him by his dirty overalls (Yes! He was wearing overalls!), and kick his smelly ass all the way across the creek. I did not shove that cheap cigarette up his nose. I did not yell at him to move his fat-fucking ass somewhere else and take his ugly-assed kids with him! Nope! I was good. I was aware of my symptoms, and stifled all of those urges ...though just barely. He was one lucky asshole.

Instead I said, "Well! Then! I guess you are not shopping, and you are bothering my customers. Move it, or lose it!"

I suppose I could have been a little more polite about it, but considering the circumstances and the  alternatives I was on my best behavior. Did I mention that I have bvFTD? I think I may have been moving towards him as I said it, but I don't exactly remember. I know I really wanted to choke the smoke out of him. He moved. Fast! Gone! Nothing left of him but a bad smell, and a cloud of smoke, and a memory. Kids too.

"Bye! Come again when you can't stay so long!"

I turned around to see 3 women standing there right behind me. They had probably heard most of what had transpired. They were giggling. I gave them a big smile, and welcomed them into the booth. What could I say? Turns out it was the woman the asshole had blown the smoke at with a couple of her friends, or maybe her grown-up kids. In any case they came right into the booth now that the asshole had moved on, and shopped around. They didn't mention anything about what transpired, but they bought a few things. I don't remember exactly what. Maybe some dip mixes.

But here is the thing. I enjoyed it! It was great fun to unleash my bvFTD on this boorish asshole. Somehow it was very satisfying. Deep-down satisfying. Exhilarating! And even better, I was able to control my symptoms, and use restraint. Maybe that is part of why it was so enjoyable. I used my bvFTD to my own advantage, maybe for the first time ever! Now, how kool is that?

I told Cindy about it when she got back from her break, but without the bvFTD connections. That asshole was probably very lucky that she wasn't there. She is a huckster! She does not have bvFTD. She would probably not have used restraint. He would probably be trying to figure out how to remove a cigarette from a left nostril right about now.

Yes it is sometimes difficult. I try to have some fun with it now and then. The alternative is all doom and gloom. It isn't going away. Fun is better.

Some days are better than others.

Comments are welcome.