E-mail: [email protected]





Ref.:
1.
http://www.docguide.com/news/content.nsf/news/8525697700573E1885256DAC004A3F38?OpenDocument&id=F6417EEC
5C48A9718525696700282E94&c=Alzheimer%27s&count=10
2.
http://www.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Committees/Peripheral+and+Central+Nervous+System+Drugs/
092403_Memantine/092403_MemantineR.htm
3.
http://www.medscape.com/viewarticle/461946


Ref. :
Schwalen S, Hammond G, Davidson M, Number needed to treat (NNT) for galantamine in Alzheimer's Disease. Abstract presented at EFNS 2003.
http://www.agelessdesign.com/news-alz-Sept-03-SPECIAL-1.htm



Ref.:
http://www.medscape.com/viewarticle/461883

Obesity in older women linked to increased risk for Alzheimer’s disease


Ref.:
http://www.thestar.com/NASApp/cs/ContentServer?pagename=thestar/Layout/Article_Type1&c=Article&cid=
1058220611150&call_pageid=968332188492&col=968793972154


Ref.:
http://www.medscape.com/viewarticle/461741?mpid=18898



Ref.:
http://www.heartcenteronline.com/myheartdr/home/research-detail.cfm?reutersid=3873&nl=4


Ref.:
1. CNS Drugs 2003;17:13:947-63. "Clinically significant drug interactions with cholinesterase inhibitors : a guide for neurologists"
http://www.docguide.com/news/content.nsf/news/8525697700573E1885256DBC00339084?OpenDocument&id=F6417EEC5
C48A9718525696700282E94&c=Alzheimer%27s&count=10
2. http://www.docguide.com/news/content.nsf/PaperFrameSet?OpenForm&refid=2&id=F6417EEC5C48A9718525696700282E
94&newsid=8525697700573E1885256DBC00339084&u=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=
PubMed&dopt=Abstract&list_uids=14533945&ref=/news/content.nsf/news/8525697700573E1885256DBC00339084?Open
Document&id=F6417EEC5C48A9718525696700282E94&c=Alzheimer%27s&count=10


Ref.:
1. NIA news release, October 21, 2003:
1.
http://www.bio.com/newsfeatures/newsfeatures_research.jhtml?action=view&contentItem=121910020&Page=1


Ref.:
Studying the Well-Trained Mind Marcia Barinaga Science 2003 October 3; 302: 44-46. (in News Focus)
http://www.sciencemag.org/cgi/content/summary/302/5642/44?maxtoshow=&HITS=10&hits=10&
RESULTFORMAT=&fulltext=buddhism+neuroscience&searchid=1069896942322_12411&stored_search
=&FIRSTINDEX=0&fdate=10/1/1995&tdate=11
/30/2003











Usefulness of acetyl-cholinesterase therapy for long-time care in Alzheimer’s disease

During the Alzheimer’s disease progression, patients loose their ability to care for themselves, such as dressing, bathing, or going to the washroom. Caregivers, becoming more and more stressed, have to choose to place their family members in specialised nursing homes. In the US, expenses in nursing homes are significant, reaching 40 000 –50 000 USD a year. Even in developing countries such as Thailand, specialised residences may require significant financial means.

The following study, funded by Esai-Pfizer, included 671 patients, who had received donepezil from less of 6 years up to more than 2 years. Patients with short drug treatment, 6 months or less, had to be placed in residences in a medium time of 3.7 years, patients receiving donepezil 9 months or more were placed after a medium time of 5.5 years. Furthermore, patients who took the drug longest, were placed in residence in an average of 21 months later than whose being treated shortest.
These results show that patients should get the drug during long time, even short-term drug intake results in modest improvements, because these small improvements are cumulating with time going.

Ref.:
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/07-01-2003/0001974777&EDATE=

Another study that time sponsored by Jansen Pharmaceuticals shows a persistent benefit from another acetyl-cholinesterase inhibitor, galanthamine. The study was double-blind, including patients suffering from mild to moderate Alzheimer’s disease and lasting 12 months. This study was complemented by an open-labelled treatment up to 36 months, thus patients being exposed to galanthamine up to 4 years.
The mean yearly decline rate reached 12.8 points as measured by the ADAS-cog score compared to the expected 24 to 36 points in a patient’s group who would not get drug treatment. Hence, galanthamine decreased the cognitive decline rate by at least 50%. This study also shows, that we cannot expect more than modest improvements for short term, but can count on cumulative long-term benefits.

Ref.:
http://64.4.26.250/cgi-bin/linkrd?_lang=EN&lah=3122f833cef1ced2380d456ddab84f33&lat=1054701888&hm___action
=http%3a%2f%2fmp%2emedscape%2ecom%2fcgi%2dbin1%2fDM%2fy%2fhcHD0ELekL0D2H0Fbhs0AC

In addition to its acetyl-cholinesterase inhibitor properties, galanthamine shows also activity on nicotinic brain receptors. The relevance of this latter feature in the slowing of the disease progression should be further investigated.
In fact, limited experience with rivastigmine, an other acetyl-cholinesterase inhibitor, like donepezil. seems also to slow down the disease progression.

Ref.:
http://64.4.26.250/cgi-bin/linkrd?_lang=EN&lah=380bd12bdee3f82a8fc5aa4d867eefb3&lat=1056136130&hm___action=
http%3a%2f%2fwww%2eagelessdesign%2ecom%2fnews%2dalz%2ehtm

Ischemic stroke may be due to genetical factors

Dr. Jerrard-Dunne and her team (USA, 2003) studied the family history of stroke of 1000 stroke patients and 800 matched controls. They segmented the patients’ group in small- vessel stroke and large-vessel stroke. The scientists noticed that the family history of stroke taking place before the age of 66 years was associated with an increased prevalence of 2.24 times for large-vessel stroke and 1-93 fold for small vessels. The family history correlation was even stronger by 3 times in patients having their first stroke before the age of 66.

Ref.:
 http://www.medscape.com/viewarticle/452974?mpid=12894

Mid-life gene changes may affect memory in later life

Scientists in the US (2003) have identified about 150 genes that affect memory of animals. These changes took place before these animals reached their mid age. The activity of these genes was not the results of mutation but was coordinated and sequential. It is assumed that similar changes take place in humans and may influence the development of Alzheimer’s disease. If the mechanism of age related cognitive decline would be better understood, then subjects at risk can be identified and preventive measures can be developed.

Ref.:
http://www.healthscoutnews.com/view.cfm?id=513093

Memantine slows the progression of moderate to severe Alzheimer’s disease

Glutamate is the main neuro-transmitter mediating the excitatory neuronal network via the N-methyl-D-Aspartate receptor (NMDA). It is assumed that overstimulation of neurones may be a contributing factor to neurodegeneration. Memantine is a NMDA antagonist, which may slow the progression of Alzheimer’s disease. Dr. Reisberg and colleagues (USA, 2003) performed a double blind clinical study comparing memantine to placebo in 252 patients suffering from moderate to severe Alzheimer’s disease during 28 weeks. The psychometric tools used were the Clinician’s Interview Based Plus Caregiver Input (CIBIC-Plus) and the change from baseline to week 28 with the Alzheimer’s Disease Cooperative study Activities of Daily Living Inventory (ADCS-ADL) modified for severe dementia (ADCS-ADLSev). At study end, the results seem to confirm a significant effect of memantine to slow the Alzheimer’s disease related cognitive decline.

Ref.:
http://www.medscape.com/viewarticle/452358?mpid=12894&WebLogicSession=Pr2AwAoQa1RX9f1jJEONtH2ah7JlPwQE
GVD730Ac26unObiWzH2u|-1396097624541369527/184161393/6/7001/7001/7002/7002/7001/-1

Compensatory brain activities among smarter patients with Alzheimer’s disease at early stage

Dr. Grady and her team (Canada, 2003) studied the compensatory brain functions of Alzheimer’s patients at early stage while they were submitted to semantic and episodic memory tests.
The study included 11 older patients with probable early Alzheimer’s disease and 12 healthy elderly subjects as a control. During the study, brain activities were monitored with positron emission tomography (PET). Each study subject was submitted to computer supported memory tests.  The semantic test consisted of words or objects appearing on the screen, participants had to press the left button of the mouse if the word or objects were associated to a living being.
The episodic test consisted of words and objects appearing either on the left or on the right of the screen, some word objects appearing more than once. Participants had to push the button corresponding to the site of words and objects having already appeared during the exercise.
Alzheimer’s patients performed usually less well than normal subjects did. However, among the Alzheimer’s patients, there was a range of success/failure from within the normal to very poor results. Those AD patients performing best were able to mobilize prefrontal activity much more intensely than the poor performers. This activity took place in the right frontal and temporoparietal areas.
According to Dr. Grady, more research would be worthwhile to explore the potential of brain compensatory activities, in order to find ways to improve and conserve this potential for cognitive rehabilitation. Dr. Grady had found in a previous study, that some healthy older adults showed similar compensatory activities, compared to younger adults, when submitted to challenging memory tests.

Ref.: http://www.sciencedaily.com/releases/2003/02/030205072742.htm

Silent brain infarcts associated with higher risk of dementia

Dr. Breteler and colleagues (Netherlands, 2003) studied the association of silent brain infarcts and increased risks to develop dementia in 1015 subjects in the population based Rotterdam study. At study beginning, the subjects were aged 60 to 90 years without dementia. At base line in the years 1995-6, the subjects were assessed with regard to cerebral MRI and neuropsychological tests. Four years later they were reassessed. During the course of the study, the subjects were monitored with regard to signs of dementia. Until study end, 30 persons develop dementia. Those persons with the presence of silent brain infarcts had more than double the risk to become demented, mostly suffering from dementia of Alzheimer’s type. Also, these subjects had steeper cognitive decline.
The authors of this study commented that additional research should be undertaken for consolidating these findings. Also the assessment of various interventions to decrease vascular risks should be included in those studies. Then, if the results are confirmed, the management of vascular risks will become an important factor for preventing dementia.

Ref.:
 http://216.33.240.250/cgi-bin/linkrd?_lang=EN&lah=acb4298daf1e67c57f4d89344d4d01b7&lat=1049735390
&hm___action=http%3a%2f%2fmp%2emedscape%2ecom%2fcgi%2dbin1%2fflo%2fy%2fhbQw0ELekL0D2H0FX8V0Ai

High blood level of sugar associated to memory impairment

Several studies have shown that diabetic patients tend to have a smaller hippocampus and less memory abilities than the age matched healthy subjects. However, the deleterious effects of elevated sugar blood levels start well before diabetes has fully developed, according to Dr. Convit (USA, 2003).
Dr. Convit studied 30 healthy subjects aged 45+. On one side, these subjects were tested on the speed of their glucose metabolization, and on the other side, they were submitted to various memory tests. Furthermore, MRI was used to measure the size of the hippocampus.
There was a correlation between the speeds of glucose metabolization, the size of the hippocampus, and the scores of memory test. In other words, the slower glucose was metabolized, the higher was the level of blood glucose, the smaller was the hippocampus, and the lower were memory scores. The US diabetes association recommends pre-diabetes testing for every subject reaching 45 years of age. If elevated blood sugar is present, it is recommended to loose weight and to exercise more. These preventive measures would improve many health aspects and prevent memory loss.
This study was based on a small subject number and should be repeated on a larger scale for confirming these findings.

Ref.:
http://hdlighthouse.org/treatment-care/care/hdltriad/exercise/updates/0043sugar.phtml

New MRI scans may be able to follow brain destruction in Alzheimer’s disease

Dr. Gilman and colleagues (USA, 2003) made MRI scans of the brain of 12 subjects with Alzheimer’s disease and 14 healthy volunteers every three months. Then, the clinicians compared together the time-lapse images. They observed that patients with Alzheimer’s disease loss 5.3 % of their brain cells per year compared to 1 % in healthy volunteers.
The losses reached even 10 % in memory brain regions. This destruction started in the memory region, followed by the areas involved in emotion, while the visual area was conserved.
This method cannot diagnose Alzheimer’s disease, which needs psychometric tests to demonstrate memory and cognitive dysfunctions. However, this serial imaging test has the potential to follow up disease slowing therapies. Furthermore, it may demonstrate if mental stimulation or physical exercise may slower the pace of this disease.

Ref.:
http://printerfriendly.abcnews.com/printerfriendly/Print?fetchFromGLUE=true&GLUEService=ABCNewsCom

Types of fat intake may be associated to various risks of developing AD

Dr. Morris and colleagues (USA, 2003) studied the eating habits of 815 residents, aged 65 years +, in a clinic in Chicago. At follow-up 4 years later, 131 subjects developed Alzheimer’s disease. Those residents eating more than 25 g daily saturated fats found in animals, such as butter had almost double the risk to develop the disease. Those eating about 14.5 g unsaturated fats such as found in fishes and nuts had 70% lower risk to develop dementia. Saturated fats promote high blood cholesterol and deposits of atherosclerotic and amyloid plaques.

Ref.:
http://216.33.240.250/cgi-bin/linkrd?_lang=EN&lah=c419bf7158b125cfdee847c2e68e7b66&lat=1048526125&
hm___action=http%3a%2f%2fwww%2eagelessdesign%2ecom%2fnews%2dalz%2ehtm

Phenserine with dual action in Alzheimer’s disease

Phenserine is a selective acetylcholinesterase inhibitor of the 3rd generation. It disappears rapidly from the blood, which makes it a very well tolerated drug. Phenserine binds, reversibly but with long-duration, on the acetylcholinesterase. Due to its binding properties, its brain/blood ratio is 10.
Dr. Greig and colleagues (USA, 2003) studied the effect of phenserine on APP in transgenic mice. They were able to demonstrate that this substance decreased the a-beta levels by more than 50%, which granted to phenserine a potential of slowing the disease. It does not interact with APP proteolytic enzymes, which may play a vital role, but by an as yet to identify mode of action on the post-transcriptional level.

Ref.:
 http://www.seniorjournal.com/NEWS/Alzheimer's/04-08-02Phenserine.htm

Axonyx, the developer of phenserine, has already performed clinical phase I trial, demonstrating that the drug was well tolerated in healthy volunteers. The company plans to initiate phase II and III trials this year, in order to study tolerability and efficacy of phenserine in patients with Alzheimer’s disease.
 
 Ref.:
http://www.axonyx.com/investor_relations/news.html#

News for April 2003

Adult bone-marrow stem cells can become neurons!

Dr. Merry and colleagues (USA, 2002) studied autopsies of 4 female infants, having received bone-marrow stem cells from male adults. These female patients received bone-marrow stem cells because they had either lymphoma, leukemia, or got an implant. Three died within 2 months after intervention, the fourth one survived 10 months. All patients exhibit y positive male cells. The one who survived longer had y-positive neurons, mainly in the hippocampus and in the neocortex. These results demonstrate that adult bone-marrow stem cells can migrate into the brain and differentiate into neurons if the patient survives long enough.
Science should find out which are the conditions to accelerate and amplify this phenomenon.

Ref.:
http://www.medscape.com/viewarticle/448187?mpid=9193

BDNF genes involved in memory

Brain derived neurotrophic factors (BDNF) influence memory in humans according to Dr. Egan and colleagues (USA, 2002). Animal studies have shown that BDNF not only are important for nerve survival but played an important role in the functioning of the hippocampus.
Dr Egan and colleagues studied 641subjects, normal subjects as a control and patients with schizophrenia and their unaffected offspring, with regard to the type of BDNF factors and their influence on memory. Met-BDNF gene has a point mutation of methionine, whereas normal BDNF gene has valine. Those subjects with two met-BDNF alleles have systematically lower test scores on tests measuring verbal episodic memory. Their scores reach 40 % while subjects with two normal valine-BDNF have scores of 70%.  Functional magnetic resonance imaging (fMRI) shows that subjects with only one allele met-BDNF gene have stimulation along the sides of the hippocampus when they are submitted to delayed recall test. This stimulation is absent in carrier of the two met-alleles.
Furthermore, NMR scans were used to measure N-acetyl-aspartate, a marker of healthy brain and a wealth of synapses. Bearers of just one met-BDNF allele have fewer markers than normal control. This level is even lower in subjects with two met-BDN alleles. The researchers labeled then BDNF with a fluorescent label. MRI scans showed that val-BDNF distributed well into the neuron body and into the dendrites.
Met-BDNF tends to make clumps in the cell body of neurons. During memory tasks, BDNF is synthesized by the hippocampal neurons to stimulate plasticity and production of new synapses. But to be effective, the BDNF factors had to be carried at the extremity of the dendrites, what is obviously deficient in bearers of two met-BDNF alleles.
Dr. Egan and colleagues are planning to make the sort of investigation in aging subjects, normal controls, subjects with depression, and subjects with Alzheimer’s disease.

Ref.:
http://www.bio.com/newsfeatures/newsfeatures_research.jhtml?action=view&contentItem=98170264&Page=1

High blood pressure leads to a higher prevalence of Alzheimer’s disease

Dr. Wu and colleagues (People’s Republic of China, 2002) follow up 16488 subjects in China, participating in a large-scale placebo controlled nutritional intervention study.  Subjects were screened for dementia by means of the Chinese Mini-Mental State Examination (CMMSE) and by the Activity of Daily Living (ADL) questionnaire. 301 subjects were diagnosed with Alzheimer’s disease. These patients were further submitted to detailed psychometric scales. Blood pressure was assessed at study beginning in 1989 and in the year 1999-2000. The studied population was segmented in high blood pressure group, borderline high pressure, normal pressure and low pressure groups. The rating scores were submitted to statistical analysis using the Multiple Logistic Regression. The study shows that the prevalence of Alzheimer’s disease is highest in the high pressure group, with a significative difference to the group of low pressure. There was a trend towards blood pressure dosing effect, the prevalence tending to increase with the blood pressure.

Ref.:
 http://www.alzheimersupport.com/library/showarticle.cfm/ID/1857

Activated Protein C may protect neurons in case of stroke

Dr. Zlokovic and colleagues (USA, 2003) have identified that a naturally occurring protein called Activated Protein C (APC) prevent neurons to die when they had been deprived from oxygen. When stroke occludes an artery, tPA can be used for reperfusing the brain tissue. But, reperfusion can in turn initiate a chain of reaction leading to oxidative stress. APC may block the apoptotic process, which leads to cell committing suicide. These scientists placed human neurons in an in vitro system of oxygen deprivation mimicking stroke-like condition. Most neuron died, however in presence of APC, most neurons survived. In vivo, APC protected neurons in a mouse model of stroke.
A semi-synthetic derivate of APC (modified by genetical engineering) drotrecogin alfa is already approved for the treatment of sepsis. However, it would be important that such a derivate could cross the brain-blood barrier or be applied by intranasal route.

Ref.:
http://www.heartcenteronline.com/myheartdr/home/research-detail.cfm?reutersid=3338&nl=3

 Skin test may be able to diagnose Alzheimer’s disease

Dr. Khalil and colleagues (Australia, 2003) may have designed a new skin test able to allow diagnosing of Alzheimer’s disease early. The test detects blood flow restriction in blood capillaries under the skin, linked to beta-protein deposits in blood vessels. This technique combines laser technology and electrical stimulation that activate a label to assess blood flow. The clinicians see that this technique has the potential to diagnose Alzheimer’s disease very early.

Ref.:
 http://www.iol.co.za/index.php?click_id=117&art_id=qw1043985420112B243&set_id=1

High blood sugar level linked to decreased memory

Diabetes is associated to a shrinking hippocampus and worsening of memory, particularly in the aging population. But when does this process begin? To answer that question, Dr. Convit and colleagues studied 30 non-diabetic but hyperglycemic subjects aged between middle aged and elderlies. They were submitted to memory tests, to tests measuring speed of sugar metabolisation after a meal and to MRI scans to measure the size of the hippocampus. The researchers noticed that the slower subjects metabolize sugar, the higher was the level of blood sugar and the smaller was their hippocampus. Conversely, smaller hippocampus is correlated with worsening of memory, also among the younger subjects. Dr. Convit stated that the tissue of slow sugar metabolizers has reduced capacity of utilizing sugar, leading to high sugar blood level. Since the population is aging and becomes obese, blood sugar problems are increasing. By exercising more and lowering the caloric intake, memory worsening can be prevented to some extend.
These study results are based on a small number of subjects; large-scale studies are needed to confirm these results.

Ref.:
http://www.nytimes.com/aponline/health/AP-Memory--Sugar.html?pagewanted=print&position=top

Inflammatory marker interleukin-6 protects brain cells

Interleukin-6 (IL- 6) is a brain protectant according to Dr. Rodriguez (USA, 2002). The surprising discovery stems from the observation that IL-6 binds to the same receptors as other agents known to promote cell survival.
Normally, IL-6 is not observed in healthy mice s’ brain. The group of Dr. Rodriguez produced several mice strains with various abilities to produce IL-6. These mice were transfected with a virus generating neurodegeneration. 9% of wild mice died after that infection while 60% of mice unable to produce IL-6 died also. When mice are infected by these viruses, astrocytes produced massive amounts of IL-6.
Dr. Rodriguez and his group are continuing their research, to develop a therapy, which will be then applied on humans. However, this will necessitate years of further research before clinical trials will be able to be started.
Since aging is associated to numerous noxious factors, which contribute to neurodegeneration, and since the number of old people is exploding, the cytokine IL-6 may play a major role in preventing or slowing down the progression of neurodegeneration. Potential applications of this therapy are seen in Alzheimer’s disease, Parkinson’s disease and multiple sclerosis.

Ref.:
http://www.sciencedaily.com/releases/2003/01/030110192631.htm


Gait abnormalities may be a sign of impeding vascular dementia

Dr. Verghese and colleagues (USA, 2002) followed up 422 non-demented subjects older than 75 years during a medium time range of 6.6 years. At the beginning of the study, 85 subjects had gait abnormalities. Until the end of the study, 125 subjects developed dementia. The group of subjects with gait abnormalities had twice the probability to develop dementia. The prevalence of Alzheimer’s disease was not influenced by the status of gait, while the probability to get vascular dementia was multiplied by more than three. The gait abnormality, which was associated to vascular dementia, was hemiparesis. Patients with hemiparesis had an increase of probability to develop vascular dementia by more than 13 times. Assessment of gait status had a specificity of 84%. However, more work is needed until a useful method will be operational, which will allow to identify subjects at risk to develop vascular dementia. This will be very useful, since effective preventive measures are already available.

Ref.:
 http://www.medscape.com/viewarticle/445234

Old people aged 100 years and more may reveal genetical clue leading to aging

Major age associated diseases such as Alzheimer’s disease and arthritis share some similar inflammatory mechanisms. Thus, people treated for inflammatory joint diseases with NSAIDs showed a lower prevalence to develop AD.
Dr. Franceschi and colleagues (Italy, 2002) monitored centenarians in order to find out what could be the conditions for this people to become old. The scientists noticed that the subjects 100 years or older had low inflammatory responses, particularly the pro- inflammatory cytokine IL-6. In addition, they have a high level of anti-inflammatory cytokine IL-10. An inbalance of cytokine IL-6 versus IL-10 may lead to age related inflammatory diseases. Cytokine IL-6 is produced in muscles and bones, and can provoke muscle atrophy and osteoporosis. Although, inflammation cannot explain everything, it may nevertheless be a major cause of the diseases.

Ref.:
http://news.bmn.com/news/story?day=030124&story=1

New neuroprotectants with potential use in Stroke, Parkinson’s disease and Alzheimer’s disease

P53 protein is commonly found at the top of a cascade leading to cell death. Dr. Craig and colleagues of the National Institute of Aging (USA, 2002) discovered inhibitors of P53 protein such as pifithrin-alpha (PFT). In vitro tests show that, when brain cells are submitted to intoxicants, they survived longer in presence of PFT. In rodent stroke models, PFT was able to limit cell destruction. Other rodent models showed that PFT seems to be neuroprotective in models of Parkinson’s disease and Alzheimer’s disease. In particular, PFT protected nerve cells against A-beta toxicity. However, further studies are needed to investigate if inhibition of P53 may cause side effects. It is known that mice having no P53 have an increased probability to develop cancer, while those with too much P53 experienced an acceleration of aging.
In clinic, the potential applications of P53 inhibitors will start first in the treatment of stroke and brain trauma. If the drugs are well tolerated, they will be investigated for long-term treatment of neurodegenerative diseases. Dr. Greig’s team is working on PFT analogues, for which they have filed patents. However, many years will be still     
needed, before they will be applied to patients.

Ref.:
http://center.acs.org/applications/ccs/application/index.cfm?PressReleaseID=2024&categoryid=21

Risk of late-onset Alzheimer ‘s disease may be related to the gene CYP46

Patients with a mutation of the gene CPY46 may be at increased risk to develop Alzheimer’s disease (USA, 2003). If this mutation goes together with the presence of APOE-4, this risk is increased by a factor of 10 compared to patients without both mutations. CPY46 is involved in the production of enzymes degrading cholesterol in the brain. In the presence of CPY 46 mutation, there is an accumulation of cholesterol and beta-amyloid proteins in the brain. This finding supports the hypothesis that cholesterol is involved in the modulation of Abeta-proteins.

Ref.:
http://www.cnn.com/2003/HEALTH/conditions/01/20/alzheimer.gene.ap/index.html

Nicotine enhances memory in AD patients

Several studies from North America and Europe tend to show that nicotine improves cognitive performance in elderly patients. In particular, when nicotine is administered
to Alzheimer’s disease patients, mistakes can be reduced by 10% to 80%. Furthermore, it has been shown in animal studies that nicotine can protect nerves against the effects of neurotoxic agents. However, various scientists do not recommend smoking because it causes many diseases and can reduce life expectancy by 7 to 8 years. Therapeutic applications use nicotine patches. However, tobacco products are very often contaminated by normonicotine, which is toxic and may contribute to neurodegeneration (See News for January here below: normonicotine in smoking may lead to metabolic diseases including Alzheimer’s disease).
In that context, it is entirely justified that drug companies are looking for synthetic derivatives of nicotine. An important feature should be that these agents are not metabolized in normonicotine!

Ref.:
http://www.globeandmail.com/servlet/ArticleNews/PEstory/TGAM/20030117/UNICO3E/Health/health/health_temp/1/1/3/

New memory tests may be useful to dedect early Alzheimer’s disease

According to Dr. Spaan (Netherlands, 2003), elderly subjects in pre-dementia state do not profit from semantic similitude. For instance, they do not remember couples of words better like pipe-cigar (category of smoking devices) or motorcycle-car (category of transport vehicles) than they remember pairs of words with no semantic links such as nail-butter. Many of those people will develop Alzheimer’s disease within two years. On the opposite, normal elderly subjects benefit of such a semantic link. Dr. Spaan studied a large group of elderly persons, who live semi-independently. Dr. Spaan submitted these persons to various cognitive tests, conducted twice, at the beginning of the study and 2 years later. She compared the scores with those of a group of persons, who have not developed AD. While episodic memory was not discriminatory, semantic memory tests were. Dr. Spaan thinks that if clinicians would use a balanced test battery which include episodic and semantic memory tests (concerning general knowledge and information), they would be able to better identify subjects who will develop Alzheimer’s disease soon.

Ref.:
http://www.alzheimersupport.com/library/showarticle.cfm/id/1869

Metanalysis confirms the efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric disorders and functional impairment in AD

Dr. Trinh and colleagues (USA, 2002) proceeded to a metanalysis of 29 relevant studies, reporting on controlled trials of patients with mild to moderate Alzheimer’s disease, treated with either a cholinesterase inhibitor or placebo. These studies were drawn from clinical data banks such as medline and the cochrane register. These studies used neuropsychiatric scales such as the Neuropsychiatric Inventory (NPI) and or the non-cognitive ADAS-scale to measure neuropsychiatric outcome. For measuring functional outcome, these studies used scales of Instrumental Activities of Daily Living (IADL) or Activities of Daily Living (ADL). The outcomes were submitted to statistical analysis (weighted mean difference method).
The metanalysis shows that there were modest but significant improvement in neuropsychiatric symptoms and in functional outcomes in those patients receiving cholinesterase inhibitors. Further studies should assess, how these improvements can be translated into benefits with regard to patient’s quality of life, time to institutionalization, caregiver’s burden.

Ref.:
 http://jama.ama-assn.org/issues/v289n2/abs/jma20041.html

Increased epinephrine in urine may be a marker of cognitive decline in elderly men

Dr. Kartamangla and colleagues (USA, 2002) have investigated 154 men and women aged 70 years or more, with exceptional mental function and had followed them up to 10 years since 1988. The researchers measured stress hormone associated epinephrine levels in the urine. Measurements took place at study beginning, 2.5 years and 7 years later. Along urinary epinephrine measurements, subjects were assessed with standard tests of language, memory, abstraction, and spatial recognition.
The study team noticed that increasing urinary level of epinephrine preceded cognitive decline in men but not in women. When concentration of epinephrine doubled, this was followed by 28-point difference in memory.
It would be interesting to investigate what triggered the increase of epinephrine in men, and then to verify if this preceding factor can be found in women, and what this factor trigger in women.

Ref.:
http://www.medscape.com/viewarticle/445169

Abeta 42 intraneuronal accumulation precedes plaque formation and may provoke synaptic abnormalities

In mice, intraneuronal increased levels of abeta-proteins were associated to cognitive dysfunction months before plaques started to accumulate. Dr. Takahashi and colleagues (USA, 2002) studied neurons of normal and mentally impaired mice as well as neurons of healthy and Alzheimer’s subjects by immuno- electronic microscopy. Intraneuronal beta-amyloid 42 were present in multivesicular bodies in normal, rats, mice, and humans. In Alzheimer’s disease, there is an increase of Abeta 42, particularly in presynaptic and postsynaptic compartments. These increased levels were associated with abnormal synaptic morphology. According to the authors of this paper, the intracellular increase of abeta 42 may play a key role in the development of Alzheimer’s disease.

Ref.:
Takahashi RH, Milner TA, et al.: Intraneuronal Alzheimer abeta 42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol, 2002, 161 (5): 1869 – 79

Memory genes might unravel new drug targets to improve memory

Short-term memory may use already available molecules. However, learning is linked to long-term memory, which needs the synthesis of new molecules. In that context, Dr. Akon and colleagues (USA, 2002) used rats, trained to find a platform for escaping water in a water labyrinth. The scientist took a sample of brain tissue in the hippocampus of trained rats and analyzed gene activity. They found about 140 genes involved in memory. They observed that a fibroblast growthfactor FGF – 18 were increased in those trained rats during learning, compared to untrained controls. They injected FGF – 18 in the brain of rats during learning phase and noticed that the learning time was decreased by half. The scientists synthesized other memory modulating substances that they patented. The authors of this paper estimate that their discovery would offer many drug opportunities to improve memory.

Ref.:
http://www.upi.com/view.cfm?StoryID=20021125-042540-7648r

Training memory may reverse age-related cognitive decline

Dr. Ball and colleagues (USA, 2002) proceeded to a study involving 2808 healthy elderly subjects within a program called ACTIVE (Advanced Cognitive Training for Independent and Vital Elderly). The participating subjects were between 65 and 92 years old and had MMSE superior to 22. They underwent 10 training sessions lasting from 75 to 90 minutes, spread over 5 to 6 weeks. The training aimed at improving verbal episodic memory, inductive reasoning, and speed of processing. 711 subjects did not get any training as control. Improvements were documented in 26% of the memory training group, 74% of the reasoning training group, and 84% in the speed training group. The levels of statistical relevance were maintained after 1 to 2 years of follow up. This improvement reverse the cognitive decline expected in subjects of this age by 7 to 14 years. Booster training of cognitive intervention improved this performance. The study group will be followed up for another 5 years in order to check if trained people had a slower cognitive decline than the untrained control subjects.

Ref.:
http://www.medscape.com/viewarticle/444448?mpid=6393&WebLogicSession=PdwehsYbfUSl91hOMaumctAhfjR4UU9o
WViJLSYZVGKWT1y8022s|1220433169361888838/184161392/6/7001/7001/7002/7002/7001/-1

Further studies on cognitive intervention in early Alzheimer’s disease had shown to be highly beneficial. Dr. Clare and colleagues (UK, 2002) have trained 12 participants with early AD and MMSE scores of 18 or above to make face-name associations, using an error less learning paradigm. This training allowed a significant improvement in recall of trained but not control items. This improvement was maintained after 6 months in absence of practice.

Ref.:
http://www.agelessdesign.com/news-alz.htm

Another study, conducted in Japan, shows that that therapeutic psychosocial intervention had significant benefits for subjects with very mild Alzheimer’s disease. Dr. Ishizaki and colleagues (Japan, 2002) studied the effect of structural psychosocial intervention in subjects with mild AD, having a Clinical Dementia Rating (CDR) of 0.5. The study contact group participated in activities in a day-care like setting once a week during 6 months. The control group had no such contact. Both groups were assessed after 9 months with regard to cognitive tests, affective scales, global clinical measurements, observation scales during the sessions, and a projective test. The contact group showed significant improvement on word fluency, global clinical measurements, and behavior. MMSE scores and digit span were significantly superior in the contact group compared to the non-contact group. Furthermore, the control non-contact group showed a significant decline on the MMSE scale compared to baseline.

Ref.:
http://www.agelessdesign.com/news-alz.htm

Early pathological events may lead to Alzheimer’s disease

Etiological factors, such as lack of mental and physical activities, lack of social interaction, inflammation, oxidative and mitochondrial stresses and high cholesterol blood level may influence the early evolution of neurodegeneration. Damages in mitochondria as well as protease inhibition may be the first sign of an impending Alzheimer’s disease, while missprocessing of APP, producing Abeta 42 and Abeta 40 with the associated plaque and neurofibrillary tangles are later manifestations of the disease.
Dr. Prasad et al. (USA, 2002) raised the hypothesis that epigenetic components of neurons, such as mitochondria, proteasomes and post-translation protein modifications are the target of noxious agents produced by inflammatory and oxidative stress. Therefore, a combination of antiinflammatories, such as NSAIDs and a mix of micronutrients, such as antioxidants and folates may be more effective than single agents to prevent or slow down the progress of the disease. However, clinical trials are needed to substantiate this hypothesis.

Ref.:
http://www.docguide.com/news/content.nsf/PaperFrameSet?OpenForm&newsid=8525697700573E1885256C9000222209
&topabstract=1&u=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12480796&dopt
=Abstract


Brain damages of professional boxers start long before clinical signs of neural and mental impairments appear

As many as 20% of retired, formerly active boxers, suffer from chronic traumatic encephalitis (CTE). Dr. Zimmerman and colleagues examined the brain of 24 active boxers, not yet having signs of CTE, and 14 controls, using a new technique called Diffusion Weighted Imaging (DWI). This technique allows showing the movement of water in the brain. The flow of water is slower through the tissues than outside the tissue. Comparing the brains of boxers to those of the controls, the brains of the former had patches of faster moving water in brain tissue, which were not visible in controls. On average, the DWI brain pictures of the boxers resembled to those of older adults, particularly those tending to develop Alzheimer’s disease. DWI detected brain damages missed by MRI.

Ref.:
http://www.medscape.com/viewarticle/444636?mpid=6393

These observations show that it would be prudent and beneficial for boxers, to receive special diets associating antiinflammatory and antioxidant agents for protecting the brain. This would be especially relevant in Thailand, where many segments of the Thai society are praising this sport (Muay Thai).

Bone marrow stem cells able to develop into new brain cells

In USA, embryonic neural stem cell research is submitted to very restricted ethical limitations. Dr Yu and colleagues (USA, 2002) succeeded to produce neural progenitor cells from adult bone marrow stem cells of rats. They extracted bone marrow stem cells that they modified by genetical engineering. They injected these modified cells in arteries of stroke model rats. Forty-eight hours later, the transplanted cells colonized the stroke related brain lesions.
Dr Yu stated, when this technique will be mature for human application, one can imagine extracting bone marrow stem cells from a given patient, engineering them into neural stem cells, and inject them in the same patient. Potential application of this technique would be to treat for instance stroke, Parkinson’s disease, and Alzheimer’s disease. Furthermore, there would be no ethical problems associated to embryonic stem cells.

Lipid metabolism and Alzheimer’s disease

Since the discovery that mutation in ApoE gene is a risk factor for Alzheimer’s disease, it has been recognized that lipid metabolism plays an important role in neurodegeneration. According to Dr. Tanaka and colleagues (Japan, 2002), aggregation of tau proteins in neurofibrillary tangles are found in both Alzheimer’s disease and in Niemann-Pick’s disease what makes think that troubles in cellular lipid transport may be involved in both diseases. Cerebrospinal fluid contains only high-density lipoproteins such as Apo E, Apo J, Apo-I and Apo A-11. These apolipo-proteins can bind to A-beta proteins and possibly participate to its disposition.
This lipid metabolism may be a therapeutic target for treating Alzheimer’s disease.
Ref.:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12373863

Plasma membrane cholesterol may protect cells from the toxicity of A-beta proteins

Dr. Arispe and Dr. Doli (USA, 2002) studied the toxicity of A-beta proteins on PC-12 cells in vitro. They noticed that these cells became resistant to the cytotoxicity of A-beta protein (1-40) and A-beta protein (1-42) when they are incubated in a medium, which increases cholesterol in the cell membrane. On the opposite, when the medium is poor in cholesterol, toxicity is increased. The cholesterol may be involved in stability and pore formations of cell membrane.
Ref.: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12374775

A disease modifier against Alzheimer’s disease enter clinical phase II

Alzhemed of neurochem (Canada, 2002) is a small organic molecule interfering in the binding of glycosaminglycans (CAGS) with A-beta amyloid protein. This binding prevents soluble amyloid to deposit in plaques. It also seems to inhibit the inflammatory properties of the soluble forms of this protein. After 8 weeks of treatment of a relevant Alzheimer’s disease mouse model, Alzhemed was able to reduce A-beta protein load by 61 % in blood plasma and by 30% in the brain. Alzamed was well tolerated by younger and elderly volunteers in a phase I clinical trial.
A phase II study in patients with Alzheimer’s disease will start soon for investigating the potential of Alzamed to modify this disease.
Ref.:
http://library.northernlight.com/FC20020930660000209.html?cb=0&dx=1006&sc=0#doc

Deleterious inflammatory response in the brain may be mediated by interleukin1-a.

Investigational research (USA, 2002) seems to suggest that interleukin 1-a may be a key protein in inflammatory responses, which damage the brain due to brain trauma, stroke, and neurodegenerative disorders.
The study group has observed that IL-1 receptors lacking mice showed much less damage than normal mice, when submitted to brain injury. When an event triggers microglia to excrete in the brain, a vicious circle may be started, which attracts and activates more microglia in the lesion site, spreading the inflammatory damage.
If this mice model is relevant, it will be worthwhile to investigate drugs that inhibit the release of interleukin 1-a and their potential to treat brain diseases linked to inflammation.
Ref.:
http://library.northernlight.com/FA20020717030002307.html?cb=0&dx=1006&sc=0#doc

Brain’s white matter may be the primary site of Alzheimer’s disease

The classical view about Alzheimer’s disease states that the disease begins in the brain gray matter because this disease is characterized by cognitive loss. Damages seen in the white matter may be secondary to the neurodegeneration of the gray matter. However, Dr. Roher and his research team (USA, 2002) have another views: demyelination starts before any clinical signs of AD have shown up.
Therefore, Alzheimer’s disease may start by a disease of oligodendrocytes, failing to produce myelin. If axons are not properly coated with myelin, the brain cannot function. Dr, Hoher’s study group made the autopsy of brain of patients with or without the disease. They observed that brain’s white matter of patient with Alzheimer’s disease had a lesser total amount of proteins, lipids, and cholesterol than the brains of the other subjects. There is also a correlation of demyelination with the apolipoprotein E phenotype. Furthermore, women tended to have more degradation of the white matter of the brain of men, which would be consistent with the higher prevalence of the disease among females.
Dr. Roher hopes that the scientific community will more focus on the white matter in the future, than done previously, since the white matter makes also up about to 50% of our brain’s volume.
Ref.:
http://216.33.240.250/cgi-bin/linkrd?_lang=EN&lah=501d7c8a701e2e64ea5c254252bb8376&lat=1032461529&hm___action
=http%3a%2f%2fwww%2eagelessdesign%2ecom%2fnews%2dalz%2ehtm


Rivastigmine may be useful for patients suffering from subcortical vascular dementia

Subcortical vascular dementia is an important subgroup of vascular dementia, which is the second main cause of senile dementia following Alzheimer’s disease. Subcortical dementia is characterized by deficient ability in executive functions, such as planning and organizing, setting goals, self-maintenance, and abstract thought. Memory is also impaired. On neurophysiological level, there is a deficiency in transmission via the acetyl-cholinergic system, as it is the case in Alzheimer’s disease.
According to Novartis sources, the company marketing rivastigmine (EXELON), 16 patients with subcortical vascular dementia have been included in a 22 months open label study, Half the patients received rivastigmine and the other half an aspirin-like medication. During the course of the study, patients were submitted to various standard tests to measure cognitive performance as well as the caregiver burden was assessed. At study end, patients with rivastigmine showed significant improvement  in executive functions compared to the control group, and significant bettering in behavior compared to the baseline. Overall patients with rivastigmine maintained their global mental and cognitive performance, while the control group worsened significantly from their baseline. Also caregivers has less stress with patient with the active drug. Although, the study group is very small, there are encouraging results. However, more clinical experience is needed for confirming these results.
Ref.:
http://library.northernlight.com/FB20021119130000060.html?cb=0&dx=1006&sc=0#doc


Science fiction close to reality?

Scientists at Duke University, North Caroline, and Cogent Neuroscience (USA, 2002) have developed a platform of rodent brain slices, kept alive during up to two weeks in a cell culture and retaining their three dimensional structure. The brain slice is bombarded with a gene gun that uses pulse of helium, to fire small gold particles coated with human DNA. This team can screen 1000 genes or compounds within 1 month. These scientists have already 5000 compounds in their stroke model, hundreds of genes and 3000 molecules in their Huntington’s disease model. They are starting to screen compounds for Alzheimer’s disease.
Ref.:
http://www.cogentneuroscience.com/

Galanthamine may be superior to donepezil in Alzheimer’s disease.

According to Shire, the marketer of galanthamine (REMINYL), this drug has proven to be superior to donepezil in Alzheimer’s disease. In a head to head rater blinded study comparing galanthamine with donepezil, patients received at random either one or the other medication. Patients were assessed by MMSE (Mini Mental State Examination) rating scale for AD in order to measure memory, orientation, and language, and by a validated computerized model from Cognitive Research Company, assessing reaction time and choice reaction time, as a measure for attention. Galanthamine improved significantly reaction time compared to donepezil after 6 weeks of treatment only. After 52 weeks, patients under galanthamine maintained their baseline values. No change of reaction time took place under donepezil during the 52 weeks of the study.
MMSE score was significantly improved under galanthamine at weeks 13 and 26. At week 52, the score was maintained at baseline. Under donepezil, MMSE score was superior to baseline at week 13, equal to baseline at week 26, and statistically below baseline at week 52.
The authors of the study concluded that galanthamine was superior to donepezil throughout the study. The improving attention effect of galanthamine has been associated to its ability to enhance activity of nicotine receptors, besides its acetylcholinesterase inhibitory action. Nicotine receptors seem to be important to maintain attention and concentration.  However, the primary endpoint, measuring the ability of patients to function, did not show a significant difference between both drugs.
Ref.: www.shire.com

Breakthrough of stem cell therapy in the nervous system

Up to now, only a few stem cells, either extracted from embryos or from adults, developed in neurons. Generally, when stem cells are implanted in the brain or in the spinal chord, they mostly develop into glial (support) cells.
A group of scientists lead by Dr. Wu (USA, 2002) treated the human fetal stem cells with compounds important for nerve cell development and implanted them into the central nervous system of rats. Most of these pre-treated cells became neurons. These new neurons were even specific to the region where they were implanted. These results in animal tests should be replicated in humans, in clinical research to demonstrate the validity of this method for initiating new therapies. The potential of this method could be to develop new neurons to treat Alzheimer’s disease, Lou Gehrig’s disease,  stroke, and spinal as wells as brain trauma.
Ref.:
http://www.bio.com/newsfeatures/newsfeatures_research.jhtml?action=view&contentItem=88520677&Page=1

Antibodies against CD40-CD40 ligands may stop Alzheimer’s disease

Antibodies against CD40-CD40 ligands are currently tested in Crohn’s disease. However, Dr. Mullan and his team (USA, 2002) injected mice, genetically modified to express Alzheimer’s disease, with anti-CD 40 antibodies. Injected mice had their amyloid plaque deposits decreased by 60%. Submitted to cognitive tests the treated mice retained their memory. The memory test consists of mice submitted to the water tank test where they have to remember the position of a hidden platform. The untreated mice did not find again thisplatform. This treatment was also effective in mice with advanced disease. An undisclosed major pharmaceutical company expressed its interest to develop this drug for patients suffering with Alzheimer’s disease.
Ref.:
http://www.upi.com/view.cfm?StoryID=20021028-123014-2588r


Gingko biloba shows benefits in cognitive impairment

Dr. Birks and her team (UK, 2002) had reviewed 33 clinical trials, identified from clinical data including the main clinical data bases of private or governmental sources within the program of the Cochrane review. Their main findings were that there were significant benefits from Gingko biloba standard extracts compared to placebo after 12, 24, and 52 weeks of treatment. There were no significant efficacy differences between daily doses of less than 200 mg standard extracts and doses superior to 200 mg. Furthermore, there were no statistical difference between placebo and active drug with regard to side effects.
The author’s conclusions were that standard extracts of Gingko biloba are beneficial and safe for treating cognitive impairment, although recent clinical trials showed inconsistent results. There is still a need of larger clinical trials with modern technology in order to identify size and mechanisms of treatment effects, because there are still no strong evidence on Gingko biloba effect on brain function.
Ref.:
1.
http://library.northernlight.com/FC20021210850000316.html?cb=0&dx=1006&sc=0#doc
2. Birks J, Grimley Evans J, Van Dongen M. Ginkgo Biloba for Cognitive Impairment and Dementia (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software.

The eye may be a window to monitor the progress of Alzheimer’s disease

Dr. Goldstein and his team (USA, 2002) observed that beta-amyloid that deposits plaques in the brain, deposits also in the eye behind the iris. Animal tests and post-mortem analysis have shown that there is a correlation between  deposits of beta-amyloid in the eye and levels of this substance in the brain. Since the brain tries to dispose at some extent beta-amyloid, the eye cannot, which represents a potential to identify Alzheimer’s disease very early and to monitor its progress, and also possibly to evaluate the effect of drugs.
Ref.:
http://library.northernlight.com/FG20021107280000019.html?cb=0&dx=1006&sc=0#doc


Moderate drinking may benefit mental speed while smoking has negative effect

Dr. Kalmijin and colleagues (Netherlands, 2002) studied smoking and drinking habits of middle aged adults. Moderate drinking improved mental and psychomotor speed and flexibility, while smoking had the opposite effect, even lowering performance of subjects, as they were older by 4 years on the average. While these effects seem to be small in middle aged subjects, they may cumulate with aging.
 The positive effect of moderate alcohol consumption may be attributed to a better cholesterol balance and possibly to thrombosis prevention. Negative effect of smoking is seen by a contributing effect in hardening and narrowing the carotid and cerebral vessels.
However, the authors of that study do not recommend moderate drinking for preventing cognitive decline, because some people may become addicted and increase their alcohol consumption. High blood level of alcohol is neurotoxic.
Ref.:
http://www.medscape.com/viewarticle/445073


Normonicotine in smoking may lead to metabolic diseases including Alzheimer’s

Normonicotine is present in any tobacco product including nicotine patches. Normonicotine persists in the blood stream and may  contribute to addiction. Normonicotine also binds to steroids and make them more toxic. Furthermore, normonicotine binds to certain aminoacids on the surface of proteins, leading to advanced glycation end products, which may contribute to diabetes, atherosclerosis, and Alzheimer’s disease. Drs. Janda and Dickerson (Netherlands, 2002) have analyzed the blood of 20 smokers and non smokers, and observed that smokers had higher levels of proteins modified by normonicotine and higher levels of advanced glycation endproducts.
These results suggest that tobacco products may increase the risk of developing senile dementia.
Ref.: 
http://www.signonsandiego.com/news/metro/20021029-9999_1m29smoke.html

News for December 2002

A consumer organization Public Citizens (USA, 2002) wrote a letter to the US Health and Human Services Secretary, criticizing the continuation of a NSAIDs study to investigating the potential of NSAIDs to prevent Alzheimer’s disease.
The ADAPT study (Alzheimer’s disease anti-inflammatory Prevention Trial) is currently lead by Dr. Breitner aiming at assessing the prevention effect of celecoxib (a selective cyclo-oxygenase inhibitor) and naproxen in non demented elderly patients, who will be followed up during 5 to 7 years. This study is sponsored by the governmental organization called the National Institute of Aging.
The consumer organization criticized the choice of celecoxib and naproxen, which may not have the potential of preventing AD according to literature search, since these drugs do not belong to the group of NSAIDs inhibiting amyloid beta-secretases. This 7 years’ study has already enrolled about 1000 patients of those 2625 planned to be included in the trial. This study should be stopped because the drugs are unlikely to have prevention properties but can provoke gastro-intestinal side effects.
Dr. Breitner replied that the consumer’s organization based their criticism on results stemming from animal studies. Therefore, the study protocol does not need to be changed.
In fact, Dr. Aisen (USA, 2002) has documented that neither rofexocib (an other selective cyclo-oxygenase inhibitor) nor naproxen had effect on cognitive decline observed during a 12 months trial. (See news for September 2002 here below “Chronic inflammation and Alzheimer’s disease).
One possibility would be to replace naproxen by either ibuprofen, indomethacin, or sulindac for the new patients to be included into the ADAPT study. These three drugs have shown to decrease A-beta 42 protein levels.

Ref.:
1.  http://216.33.240.250/cgi-bin/linkrd?_lang=EN&lah=d1adee60f69272cac75968ca8c63084f&lat=1031248743&hm___action
=http%3a%2f%2fmp%2emedscape%2ecom%2fcgi%2dbin1%2fflo%3fy%3dhUan0ELekL0DZW0FERH0AQ
2. http://www.bu.edu/news/releases/2001/1-29-alzheimers.htm

Memantine added to donepezil shows additional benefits in Alzheimer’s disease

In a previous announcement here below it has been referred that memantine was effective in lowering the need of care among patients afflicted by moderate to severe Alzheimer’s disease. (See news for September 2002 “Memantine reduced the time of care in advanced Alzheimer’s disease) In the comments following this message it was hypothesized that the addition of memantine, an NMDA-antagonist) to an acetylcholinesterase inhibitor may be more effective than the single drugs.
The following announcement seems to bring the proof that the combination may be beneficial.
Forest laboratories (USA, 2002) announced that a 6 month double blind clinical trial seems to prove that the addition of memantine to patients receiving a standard therapy of donepezil not only slowed down the rate of decline but also improved cognition.
The study included 403 patients with moderate to severe Alzheimer’s disease who was randomized to receive either memantine or placebo in addition to their standard treatment with donepezil. Primary outcome was the assessment of the Severe Impairment Battery (SIB), which measures cognition, the Alzheimer’s disease Cooperative Study Inventory Activity of Daily Living (ADCS-ADL) and a physician’s global assessment (CIBIC-Plus). After 6 months, patients treated with memantine had a statistically superior score.
Memantine will be submitted to the US-FDA for registration by end of this year. Forest Laboratories wants to include results of new clinical trials near to completion in the USA. The company hopes to broaden the indication range of this drug. Memantine is already available in European Countries.

Ref.:
http://biz.yahoo.com/djus/020910/1119000419_1.html

Chronic inflammation and Alzheimer’s disease
There are many published documents linking chronic inflammation and higher risk to develop Alzheimer’s disease. There is the activation of the complementary inflammation reaction present in the brain of AD patients. Furthermore, higher levels of IL-1, IL-6 and TNF factors have been observed in the serum and brain extracts of AD patients. These higher levels of inflammatory agents have been associated to the accumulation of amyloid deposits, building up senile plaques. Epidemiological data of patients with chronic arthritis treated long-term with NSAIDs have shown that this group of patients had lower probability of developing AD.
These findings prompted Dr. Aisen and colleagues (USA, 2002) to conduct a clinical trial comparing the effect of rofecoxib, a selective cycloxygenase – 2 inhibitor, naproxen, and placebo in 351 patients suffering from mild to moderate Alzheimer’s disease. The treatment lasted 12 months and various psychometric instruments such as ADAS-Cog scale were used to measure changes of cognition. Secondary outcome measurements were included such as daily activities and time to institutionalizing and death.
At the end of the study period the average ADAS-Cog score decline from baseline was 5.69 in patients with placebo, 5.77 in patients with naproxen and 7.63 in the rofecoxib group. The were no significant differences between the various treatment groups with regard to primary and secondary outcomes, although the rofecoxib group showed a trend to worse outcomes when compared to the placebo group.
Ref.:
http://216.33.240.250/cgi-bin/linkrd?_lang=EN&lah=54cd2d836b44538aec400bcb9bdf0f83&lat=1029005875&hm___action
=http%3a%2f%2fmp%2emedscape%2ecom%2fcgi%2dbin1%2fflo%3fy%3dhQdx0ELekL0DbH0FKbo0AT

In another study, Dr. Weggen and colleagues (USA, 2001) studied the effects of ibuprofen, indomethacin, sulindac, naproxen, aspirin, and celecoxib on the processing of amyloid precursor proteins in cultured cells. They observed that only ibuprofen, indomethacin, and sulindac decreased A-beta 42 protein. The other agents had no such effect. Thus, it seems that only a part of NSAIDs may be effective to prevent AD, this independently of their cyclooxigenase-2 inhibitory properties. It would be interesting to check and evaluate clinically the potential of these three active NSAIDs to prevent or slow down  the cognitive decline rate in a clinical study similar to that of Dr. Aisen.
However, the inflammatory component of AD is still not addressed to. An interesting venue would be to test to what extent omega-3-fatty acids, such as lipids found in fishes can slow down the decline rate of cognition. The rationale stems from published data showing that meals rich in fish may decrease the risk of developing Alzheimer’s disease.
The omega-3 fatty acids have inhibitory properties on the biosynthesis of inflammatory cytokines.
Ref.:
http://216.33.240.250/cgi-bin/linkrd?_lang=EN&lah=5854945288d23db05883c7d9d588a908&lat=1029178344&hm___action
=http%3a%2f%2fwww%2emedscape%2ecom%2fviewprogram%2f1972%3fmpid%3d2193


Galanthamine seems to lower the cognitive decline rate in Alzheimer’s disease.
Dr. Wilcock and colleagues (UK, 2002) studied the effects of galanthamine on the rate of cognitive decline and followed up 491 patients, suffering from mild to moderate Alzheimer’s disease during 36 months in an open labeled study. About 2/3 of patients completed this trial. In this group of patients, the cumulative rate of decline has reached 12 points from the baseline on the ADAS-Cog scale. Without treatment, the expected decline score would have been from 21 to 27 points.
The authors concluded that the treatment with galanthamine should be as early as possible and be maintained as long as possible because the benefits provided by that drug is sustained.
Ref.:
http://216.33.240.250/cgi-bin/linkrd?_lang=EN&lah=f58479f2c292c40b18e266a8d1210fc8&lat=1029178000&hm___action
=http%3a%2f%2fmp%2emedscape%2ecom%2fcgi%2dbin1%2fflo%3fy%3dhQdx0ELekL0DbH0FKbr0AW

Memantine reduced the time of care in advanced Alzheimer’s disease
Memantine is an NMDA-antagonist. It has proven to decrease cognitive decline in patients with Alzheimer’s disease.
Dr. Wimo and colleagues (Sweden, 2002) have studied the effect of memantine on care time in patients suffering from advanced Alzheimer’s disease. A group of 252 patients were treated either with active drug or placebo during 28 days. The group under active drug needed 52 hours less hours per month in intensive care than patients receiving placebo.
Ref.:
http://216.33.240.250/cgi-bin/linkrd?_lang=EN&lah=42aaf78a31bfa6e5bc281f5b6e65010c&lat=1029092681&hm___action=
http%3a%2f%2fmp%2emedscape%2ecom%2fcgi%2dbin1%2fflo%3fy%3dhQdx0ELekL0DbH0FKbq0AV

Memantine does not act on cholinesterases like the other newer anti-Alzheimer drugs, but modulates glutamate levels. This neurotransmitter is neurotoxic when present in excess in the brain. That would be interesting to study the combination of memantine and an acetylcholinesterase inhibitor. May be the combination may be more effective than the single drugs.

Prevention of neurodegenerative diseases and stroke by statins: a panacea with risks?

The use of statins as preventive agents to curb cognitive decline and stroke has become popular. Clinical observations have shown that cognitive decline due to Alzheimer’s disease or vascular dementia due to cerebrovascular diseases has decreased for patients treated with statins.
With regard to the basic mode of action, statins inhibit HMG-Co A reductase. This enzyme intervenes in both metabolic pathways, that of A-beta protein and that of cholesterol. The metabolic pathway of A-beta protein influences of course the evolution of Alzheimer’s disease, while that of cholesterol influences the evolution of vascular diseases such as atherosclerosis. Furthermore, cholesterol interacts with the metabolism of A-beta protein. (Ref. 1: Statins may decrease the prevalence of Alzheimer’s disease, news for November 2001 further down on this page)

Statins contribute also to maintain the right levels of total and LDL cholesterol, which slow the cognitive decline of elderly women. Dr. Yaffe and colleagues (USA, 2001) monitored 1037 postmenopausal women below 80 years at baseline, who had suffered from coronary disease, but with no cognitive impairment at that time. At 4 years follow-up, 79 women became cognitively impaired. Women with the highest level of LDL – cholesterol and total cholesterol had the worst performance on the Modified Mini Mental State Examination (3 Ms). Women, who hat no increase of the LDL – level during these four years performed better than those having their level increased. Reduction of the levels of total and LDL – cholesterol resulted in a decreased probability of getting cognitively impaired by 50% during these four years.
 Based on these results, the investigators administered statin to 583 women for at least four weeks. There was a small, but significant, increase of cognitive performance as measured by the 3 Ms, compared to the group of women, not receiving that medication.
Ref.:
http://www.medscape.com/viewarticle/430115?srcmp=neur-031502&WebLogicSession=PJyLo58j6HK4jlb5o3OSTBgXz2OU
pJnIIeeHhZGGEO12v2ZhrZo5|-6899348335799429105/-1408233357/6/7001/7001/7002/7002/7001/-1

Furthermore, there is a positive interaction between statins and the beta – blocker metaprolol for fighting against atherosclerosis, according to Dr. Hulthe and colleagues (Sweden, 2001). They followed up 92 hypercholesterolemic patients, who were already treated with statins. These patients received either metoprol or placebo and the beginning of this study and were maintained on statins. Furthermore, the thickness of their blood vessel intima (IMT) was measured. Both groups did not differ with regard to their lipid blood value.
After 1 year of treatment, the thickness of IMT decreased in the group treated with metoprolol. After 3 years, this decrease was significant, the risk of stroke and cardiac events decreased also. The authors’ hypothesis was that the psychosocial stress promotes injuries in the intima of vessels, which in turn stimulate deposition of atherosclerotic plaques. Metoprolol decreased the effects of psychosocial stress, hence protected the vessels.
Ref.:
http://www.medscape.com/viewarticle/425193

Documentation is increasing showing the favorable role of statins, preventing neurodegeneration and cerebrovascular diseases, however at a cost. There is a risk of peripheral neuropathy associated with the exposure to statins. This risk increases with the duration of exposure according to Dr. Gaist (Denmark, 2002). Due to the important benefits of statins, Dr. Gaist does not recommend not to use this kind of drugs but physicians should be aware about this risk, be watchful. Should first symptoms of peripheral neuropathy appear in a given patient, the doctors ought to reevaluate the use of that drug in this patient.
Ref.:
http://www.medscape.com/viewarticle/433446?srcmp=neur-051702&WebLogicSession=PO7W1JMemUx47c5LPlUVg47rdB
v5XDwxPQHKFCQlvCgF1klqPxrx|-4691953477852666338/-1408233356/6/7001/7001/7002/7002/7001/-1


Diverse neuroprotective qualities of various tea brands

Regular consumption of tea has been hailed as lowering risks of vascular disorders and neurodegenerative diseases due to their antioxidant properties.
Teas, particularly green teas, have ingredients known as polyphenols, which act as antioxidants, in particular catechins, flavonoids and thearubigins.
Dr. Henning (USA, 2002) and colleagues analyzed the catechin content of 20 common green and black tea brands, sold in the USA. They brew them during 3 minutes, then they measured the catechin content. The antioxidant concentrations were within the range of 210 mg down to 10-mg according to brands. Ice teas had virtually no antioxidant properties.
It is believed that green teas have more antioxidants than black teas, but this study showed that there was not always the case. The authors of that paper recommended that the American Food Administration should require from the producers of branded teas to state the antioxidant content of their teas. This, so more as many producers are advertising their products to be good for preventing vascular and neurodegenerative diseases.
Ref.:
http://www.heartcenteronline.com/myheartdr/home/research-detail.cfm?reutersid=2373

 
Metanalysis shows that citicoline has beneficial neuroprotective activities in stroke patients

Dr. Warach and colleagues (USA, 2002) made the first analysis reported in this note. They presented results of 214 stroke patients, of which 41 received 500 mg citicoline daily for 6 weeks, 62 got 2000 mg of citicoline, and 110 controls with placebo. The clinicians scanned the patients by diffusion-weighted MRI within 24 hours after stroke and a second time 12 weeks later. At the end of the study period, patients with placebo had their infarct size increased by 85%, patient with 500 mg citicoline by 34% and patients with 2000 mg citicoline by 2%.
Another metaanalysis was performed by Dr. Jeffry and colleagues (USA, 2002), who pooled data from eight clinical trials, involving 1171 stroke patients treated with citicoline and 892 controls with placebo. They noticed that citicoline reduced morbidity and mortality by 10%.
Ref.:
http://www.heartcenteronline.com/myheartdr/home/research-detail.cfm?reutersid=2311&nl=1

However, there are big differences between both studies, the latter one having more inhomogeneous clinical settings. Probably, early treatment with drug and duration of treatment may be beneficial, especially in cases of secondary ministrokes. In the latter case, we may rather address prevention with “soft drugs” also observed in cases of vitamin E and C intake.

IV-magnesium may trigger spectacular recovery in stroke patients

Neuroprotection by magnesium may be due to various properties of magnesium. Animal studies have shown that magnesium can promote vasodilatation, which in turn increases cardiac output and blood flow in the penumbra and prevents cerebral vasospasm. Furthermore, it is a non-competitive blocker of NMDA receptors. In animal, magnesium protects the neurons against ischemic cascade and even against direct NMDA injection in the animal. It is also an antagonist of calcium entry into cells through various ion channels.
Ref.: mg neuroprotection01
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11589925&dopt=Abstract

Dr. Saver and colleagues (USA, 2002) performed an open-labeled trial on 20 acute stroke patients in administering magnesium by intravenous route already in the ambulance. 25% of patients received magnesium I.V. within 1 hour after stroke and 70% of patients within 2 hours. 25% of patients experienced a spectacular recovery, all having ischemic stroke. It seems that this treatment had no side effects in other types of stroke. If this is confirmed in controlled studies, magnesium I.V. can be administered to patients before having been submitted to CT.
This pilot study is the start of an extended controlled trial, which will include 1250 stroke patients. This study will be run by the UCLA-Stroke Center in the USA.
Ref.:
http://www.neurosurgery-neff.com/IMAGES.html

Urine test may reveal patients at risk to develop Alzheimer’s disease

Dr. Practico and colleagues (USA, 2002) analyzed urine samples with regard to isoprostane of 50 patients with probable Alzheimer’s disease, 33 patients with MCI (Mild Cognitive Impairment), and 40 healthy volunteers. After 2 weeks, the clinicians took a second urine sample and this time a CSF sample from 28 AD patients, 17 MCI patients, and 18 controls. They found that isoprostane levels were significantly higher in patients with AD and MCI compared to controls.
The hypothesis of the basic rational of this test related to isoprostane being a metabolic product of body lipids degraded by free radicals. Since there is an oxidative stress taking place in MCI and AD, there is also a production of high amount of free radicals. Lipids are attacked and isoprostane accumulates in CSF (Cerebro Spinal Fluid), in blood and in urine. At follow-ups, MIC patients with high levels of isoprostane converted to Alzheimer’s disease.
May be other flare-ups of inflammation can produce elevated levels of isoprostane.
If this test will be further developed and documented, with proof of its usefulness in diagnosing people at risk to develop AD, this first non-invasive test would be a major progress at diagnosing subjects at risk to get Alzheimer’s disease.
Ref.:
 http://www.docguide.com/news/content.nsf/news/8525697700573E1885256BD700575F3A?OpenDocument&id=F6417EEC
5C48A9718525696700282E94&c=Alzheimer%27s&count=10

News for June 2002