The measurement of biomarkers will be useful for grading disease response to treatment.
There is an active research on this field, but to my knowledge studied biomarkers - functional neuroimaging, amyloid-beta, tau, oxidative stress, mitochondrial/metabolic changes and cell-cycle processes, autoantibodies - remain a matter of research rather than clinical practice.
[18F]flutemetamol has a high specificity and sensitivity in the detection of beta-amyloid plaque in the in the field of Alzheimer's disease (AD).
I hear long time ago, that the concentration of some molecules in the cerebrospinal fluid at brain level decresed
This is an area of very active research! The biomarkers that are currently being studied most actively are CSF levels of A-beta and phospho/Tau. These have been shown to be linked to disease progression, and have been and are being used in drug trials. However, their value in measuring drug responses is still not demonstrated. You might want to visit Alzforum.org which has great info on these and other possible biomarker approaches.
It is important to emphasize that although a lot of progress has been made in the field of biomarkers for Alzheimer's disease, and that these have even been included in the new criteria for AD, the relevance of such biomarkers is predominantly research orientated. At this stage, when the discovery of a truly effective treatment remains elusive, there is little clinical relevance to the biomarkers (both CSF and neuroimaging).
As far as I know, biomarkers are still used just as diagnostic tool. Its benefit regarding treatment response and follow up is a matter of discussion and further investigation is needed.
Indeed. This is a most active research area. With the disease-modifying therapies becoming a real perspective, the need for improved accuracy in early diagnosis, and in pathophysiological changes becomes compelling. A number of brain imaging methods have already begun to show promises as biomarkers.
MRI technology has produced interresting results, but does not seem to be sensitive enough to detect subtle neuronal changes such as those known to occur in AD.
PET imaging seems as a more promising avenue. The Pittsburgh Compound-B (11C-PIB) has been the most studied. It binds specifically to the A-beta protein, and was found capable of distinguishing between AD and control subjects, but there is no correlation between uptake and severity of the disease. Other compounds such as [18F]FDDNP can also target the neurofibrillary tangles in addition to amyloid plaques. However, [18F]FDDNP-binding does not seem capable of distinguishing between mild AD and normal aging. This reduces the usefulness of such compounds, because one of the most important functions of biomarkers should be to accurately reflect AD clinical outcomes. In this context, a PET radiotracer quantifying acetylcholine (ACh) innervation density would be of particular interest as a biomarker, because the topography and severity of the ACh cell loss is known to correlate well with the symptom severity in AD, and allows distinction between AD and other dementia. To my opinion, the [18F]FEOBV appears as the most promising one. Its sensitivity and reliability has been demonstrated in animal but not in human yet.
Are there any specific or general biomarkers for following up Alzheimer's Disease treatment?
There is no treatment for AD, actually.
The best way to follow-up patients with Ad and to assess their response to treatment is by means of cognitive and functional assessments. There is insufficient evidence to support the use of biomarkers for following-up AD patients clinically.
The biomarkers evaluated neurodegeneration via atrophy on magnetic resonance images, neuronal injury via cerebral spinal fluid t-tau, brain amyloid-b load via cerebral spinal fluid amyloid-b1–42 and vascular disease via white matter hyperintensities on T2/proton density magnetic resonance images. You can search for specific biomarkers easily..
Very opportune question. Just appeared in PubMed, by Karl Blennow et al. "Effect of Immunotherapy With Bapineuzumab on Cerebrospinal Fluid Biomarker Levels in Patients With Mild to Moderate Alzheimer Disease.", in Arch Neurol 2012 - Early view (PMID: 22473769).
I do not think amyloid related any bio-markers can be used as a effectiveness of the treatment in dmentia including AD. Moreover, this type of work (clinical as well as basic research) not only able to give any benefits regarding AD fields but also blocks more effective treatment strategies against this devastating diseases.
I think that, as there is no effective cure and medications for AD an early diagnosis for the disease trough some biomarker (such the reduced level of 42-amio-acid beta-amyloid and the increase in tau - protein in the cerebrospinal fluid) beside the use of neuroimaging and PET,their relevance should be actually considered more research related and aren't important for the prognosis and therapy response
The measurement of specific biomarkers catching the impact of disease modifying agents is mandatory. These biomarkers will not necessarily be the same we use for diagnostic purposes - Abeta42, total and phospho-tau.
The highest achievements to this respect have been reached so far by the swedish group leaded by Erik Portelius, who could identify the specific amyloid fragments which reflect the impact of the anti-amyloid agents - BACE inhibitors and gamma-secretase inhibitors and modulators.
Go to Pubmed and see Portelius et al. publications.
To my knowledge AD is not curable disease, at least not yet. The only process of management of the disease at the moment is to minimize the suffering of the patient, and may be delay the deterioration period, hence I can’t see any effective follow up process, but I guess Imaging would give some guidance of the level of AD, but I can't think of any real Biomarkers for that, yes Abeta42 and tau protein would give you some idea but I do not think that they would be considered as a biomarkers for treatment follow up, simply because no real treatment exist at the moment.
I have specific comments:
Fundamental problem with this manuscript appeared to be nosological definition of the AD. Because accumulation body of clinical as well as experimental study already demonstrated that deposition of amyloid beta appeared to be as a consequence but not reason for the development of AD. I it is very unfortunate that current most accepted theory of Alzheimer Disease is Amyloid Theory:
a) The finding of amyloid-beta (Aβ) deposition in AD brains after death led to the so-called “amyloid hypothesis”.
b) For over a decade, the amyloid hypothesis has so influenced and guided research in the field of Alzheimer dementia that many workers regard it as the gold standard of scientific investigation.
c) We have extensively reviewed the literature which claims that AD is caused by the deposition of Aβ within structures called senile plaques that invade AD brains and that such plaque formation then leads to further abnormalities within the nerve cells, eventually killing them.
d) We have found little evidence to support this claim and ample evidence to question it. For example, the amyloid hypothesis has been criticized because its research findings up to now have not generated any benefits in the clinical management and treatment of AD patients nor to an understanding of how the elderly are preferentially affected.
For the additional information I strongly suggest the following excellent comments regarding the role of amyloid beta in the pathobiology of AD:
http://hypothesis.alzforum.org/swan/browser/showEntity!showHypothesisRGraph1.action?objectId=urn%3Alsid%3Aswan.org%3Acomment%3Af078cafb-5e0e-4fa7-9d32-6da7ac314356
I do not agree completely. Anything related to amyloid just wasting time and money. Moreover mouse it is not human. IN addition, peoples with full amyloid on the brain has no any mental retardation. Moreover, in APOE mouse model we have already showed that mitochondria as a energetic substrate are primary responsible for the pathology and by using specific mitochondrial antioxidants we were able to restore memory function and omit pathology. Please check the following paper:
The effect of acetyl-L-carnitine and R-alpha-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer's disease.
Shenk JC, Liu J, Fischbach K, Xu K, Puchowicz M, Obrenovich ME, Gasimov E, Alvarez LM, Ames BN, Lamanna JC, Aliev G.
J Neurol Sci. 2009 Aug 15;283(1-2):199-206. Epub 2009 Apr 1.
PMID: 19342064 [PubMed - indexed for MEDLINE] Free PMC Article
Please take and look amyloid based theory and benefits for AD patients. Any positive changes?
Even if we are going to agree with amyloid theory and treatment based on this I wish to ask you one simple question. If we remove amyloid do you think brain has to be empty? What's type of cells going to make neurotransmission?
Please check this latest paper:
Bragin V., et al. A 60-month follow-up of a naturalistic study of integrative treatment for real-life geriatric patients with depression, dementia and multiple chronic illnesses. Open Journal of Psychiatry, 2012, vol.2, 129-140.
For diagnostic use, brain image such as PIB PET or fMRI are helpful, while CSF biomarkers such as beta-amyloid (especially ratio of 42/40), total-tau and p-tau are generally recognized. But for treatment, I think the most important mark is cognitive function of patient, which is the terminal goal of therapy.
Dear colleagues,
Thank you,
I will be pleased to achieving more information about biomarkers in this field of neuroscience.
The common biomarkers for Alzheimer's disease are Beta-amyloid and Tau measured in cerebrospinal fluid. In people with Alzheimer's disease their cerebrospinal fluid contains a reduced level of 42-amio-acid beta-amyloid and an increase in tau protein. Other frequent biomarkers are neural thread protein/AD7C-NTP measured in either cerebrospinal fluid or in urine, PIB PET and brain volumetric changes observed using repeated MRI sequencing. The only problem with these biomarkers for Alzheimer's disease is that there are not always reliable and there are extremely expensive.
Some interesting papers on brain volume changes (the less invasive form of investigating disease progression)
Freeborough PA, Fox NC. Modeling brain deformations in Alzheimer disease by fluid registration of serial 3D MR images. J Comput Assist Tomogr. 1998 Sep-Oct;22(5):838-43.
Freeborough PA, Fox NC. The boundary shift integral: an accurate and robust measure of cerebral volume changes from registered repeat MRI. IEEE Trans Med Imaging. 1997 Oct;16(5):623-9
Thank you very much, Prof. Aliev. I'm a Computational Neuroscience PhD student and my project is about Alzheimer. I am very interested in others theories about Alzheimer Disease besides Amyloid Theory. Can you suggest me other papers?
It depends on whether the treatment is for people who already have AD or MCI or people who are at high risk for AD. Different biomarkers show more change at different points in the disease process, so if you are looking at presymptomatic treatments, CSF amyloid-beta markers may be a useful tool, while if you are studying people who already have moderate AD, I agree with Dr. Chong that cognitive function is a better marker since at that point, the brain has already undergone such destruction, much of which is likely irreversible. fMRI is useful in that it is very sensitive to change, but it is also very sensitive to many factors that may not be of interest to you (like anxiety level, caffeine intake etc.). It is also more difficult to interpret than many other measures. It makes sense to choose a biomarker that is likely to be dynamic for the stage of disease which interests you. This article may help:
Arch Neurol. 2011 Dec;68(12):1526-35. Epub 2011 Aug 8.
Evidence for ordering of Alzheimer disease biomarkers.
Jack CR Jr, Vemuri P, Wiste HJ, Weigand SD, Aisen PS, Trojanowski JQ, Shaw LM, Bernstein MA, Petersen RC, Weiner MW, Knopman DS; Alzheimer's Disease Neuroimaging Initiative.
Antioxidant Status and Energy State of Erythrocytes in Alzheimer Dementia: probing for markers.
Kosenko EA, Aliev G, Tikhonova LA, Li Y, Poghosyan AC, Kaminsky YG.
CNS Neurol Disord Drug Targets. 2012 Sep 17. [Epub ahead of print]
Dear all, please keep in your mind. Amyloid beta has nothing to do with the cognition. For the more detail please check the above mentioned several key publication including these papers:
Aliev G, Palacios H, Gasimov E, Solis Herrera A, Leszek J, Gokhman D, Bragin V, Obrenovich M : Comment on Holmes et al hypothesis "Plaque removal is not enough to halt progressive neurodegeneration in Alzheimer Disease." In: http://hypothesis.alzforum.org/swan/browser/showEntity!showHypothesisRGraph1.action?objectId=urn%3Alsid%3Aswan.org%3Acomment%3Af078cafb-5e0e-4fa7-9d32-6da7ac314356
Bragin V. and Aliev G. Progression of Cognitive Function after Integrated Treatment Approach in Demented and Clinically Depressed Patients. In: The Role of oxidative stress, mitochondria failure and cellular hypoperfusion in the pathobiology of Alzheimer disease. 2010; ISBN: 978-81-308-0367-8; Editors: Aliev G., et al., Publisher Research Signpost, Inc. 2010, Chapter 15, PP. 317-325.
Bragin V., Chemodanova M., Bragin I., Dzhafarova N., Mescher I., Chernyavskyy P., Obrenovich M.E., Palacios H.H. and Aliev G. A 60-month follow-up of a naturalistic study of integrative treatment for real-life geriatric patients with depression, dementia and multiple chronic illnesses. Open Journal of Psychiatry, 2012, vol.2, 129-140.
Aliev, G. “The Role of Oxidative Stress, Mitochondria Failure, and Cellular Hypoperfusion in the Context of Alzheimer Disease: Past, Present and Future”. Monograph Book: Nova Science Publishers, Inc., New York, 2012 ISBN: 978-1-61942-878-2. (in press). https://www.novapublishers.com/catalog/product_info.php?products_id=31801
Kaminsky Y.G. Poghosyan A.C., Tikhonova L.A.., Palacios H.H., M.A. Kamal, Kosenko E.A. and Aliev G. Glycolytic and Proteolytic Metabolism in Erythrocytes from Elderly and Demented patients. American Journal of Neuroprotection and Neurogeneration American Journal of Neuroprotection and Neurogeneration, 2012 (in press).
I think so far no blood biomarker is now evident for its association with AD. Beta amyloid, Tau protein, iNOS expression, asymmetric dimethyarginine changes in CSF are all associated with the disease, but I think they cannot be considered biomarkers for prognosis or monitoring.
Biomarkers aim to detect or shown the "Alzheimer's disease biological process" whereas the current medications for AD are symptomatic - i.e., their target effect is not the AD process as such, was it then deposition of amyloid ore anything else. Therefore, it is not conceivable that biomarkers could show the effect of current medications at the biological level. The clinical condition of the patient, instead, can be monitored by clinical testes / follow-up..
Izzettin's comment is very useful and it will be interesting to see his results. As we know the debate is whether Abeta is causative or whether it is an "innocent bystander" or a side product of another process. The clinical studies aimed at Abeta, such as those targeting gamma secretase, are rather disappointing. There is clearly a long way to go until we achieve an effective treatment for this devastating disease.
I agree with Aliev as a researcher who works with cognitive stimulation and rehabilitation, in my opinion probably there is a genetic Alzheimer Disease and a different sindrome "Multifactorial Cognitive Disease" (MCD), with a wide range of presentations and influences during life and this condition can be called Dementia if it becomes sufficiently severe according to what we define as dementia.
There is an interesting new pulication from the ADNI group. They idenitified 4 different proteomic signatures, each using 5 to 14 analytes, that differentiated AD from control patients with sensitivity and specificity ranging from 74% to 85% (Alz Dis Assoc Disord 2012, Sept 27). I guess that means that we have no single serum biomarker that we can use in clinic. We can cintinue to measure the MMSE, the FAST, and the CDR. We can continue ask questions from the NPI, so that we are treating "sundowning" when those symptoms should arise. I tell families that cholinesterase inhibitors are for keeping patients at home for longer periods of time (1.5-2 yrs), not for helping them score better on our tests.
I think that CSF amyloid beta 42/40 could be use as predictive biomarker to follow the treatment but you must measure the predictiveness curve to confirm this suggestion
Izzettin of course visualization of the plaque could be highly predictive but really Iam a biochemist working on autistics and always think about plasma and CSF biomarkers but you are right but I think that relative ratio of Myloid 42/40 together with visualization could be helpful to measure the efficacy of the treatment strategy
Dear All, the paper suggested by Linda Hershey is intriguing indeed. The research on plasma markers is obviuosly appealing: yet, as far as I know - also from Linda's related bibliographies - those markers are still unable to predict conversion from MCI to AD: therefore, it could be too early to exploit them for grading disease response to treatment.
Happy new year to everybody, Mauro Colombo
Yes I agree with your opinion. We have to use complex tools to make judgment regarding diseases diagnosis!
Thank you so much Cristina for your precious hint.
As far as I could see, aMCI persons didn't receive any specific treatment: is it ?
Here is a good reference from David Holzman's group about serum biomarkers in AD:
Neurobiol Disease 2009;35:128-140. Their conclusion was that there was little consensus about the relationship between serum A-beta levels and disease state, due to different assay methods and different patient selection criteria. Another study came to the same conclusion (Oh et al, Neuromolecular Med 2008;10:195-207).
dear Cristina,
I can just report PLoS ONE sept 2010, vol 5, issue 9, e 12244 [about a randomized controlled trial on vit B slowing accelerated brain atrophy in MCI]
Relationships between amyloid and cognitiion are complex indeed, as Marisol & Gjumrakch Aliev underscore [Lancet Neurol dec 2012, 11(12): 1057-65]
Please keep in your mind, amyloid is consequence but not reason for the cognition or dementia.
thank you so much Cristina:
indeed, I've found the same paper browsing in the web stemming from your previous hint, and I've sent the reference to the biologists working at "Golgi Cenci" Foundation [led by Antonio Guaita, see ResearchGate, for "InveceCe.A" study].
That means relevant literature emerges,
Mauro
The main AD biomarkers currently used reflect the underlying disease processes and are not altered by clinically available drugs since these are not disease-modifying. But there are several studies showing that anti-Abeta drugs under development impact CSF biomarkers. These biomarkers are currently useful only for drug development, but if (when?) such drugs become clinically available it is possible that they could help clinicians to determine treatment response in individual patients.
For this discussion it is useful to distinguish between primary and secondary pharmacodynamic biomarkers. Primary pharmacodynamic biomarkers are direct measurements of the drug target. Secondary biomarkers reflect processes downstream of the drug target. For a drug directed against Abeta metabolism, primary pharmacodynamic markers may include CSF Abeta (perhaps distinct isoform) or sAPP levels (several BACE1/gamma-secretase inhibitors/modulators alter CSF Abeta levels). For the same drug, secondary pharmacodynamic markers may include CSF tau (there is some evidence that Abeta immunization may reduce CSF tau levels, indicating a treatment effect on axonal loss downstream of Abeta pathology).
dear all, please let me highlight Mauro
Neurology. 2012 Sep 11;79(11):1161-7. doi: 10.1212/WNL.0b013e3182698d4a. Epub 2012 Aug 29.
Aβ-amyloid deposition in patients with Parkinson disease at risk for development of dementia.
Petrou M, Bohnen NI, Müller ML, Koeppe RA, Albin RL, Frey KA.
Source Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, USA. [email protected]
Abstract
OBJECTIVE:
The aim of our study was to examine the relationship between corticostriatal Aβ-amyloid deposition and cognitive dysfunction in a cohort of patients with Parkinson disease (PD) at risk for dementia.
METHODS:
This was a cross-sectional study of 40 patients with PD with mild cognitive impairment (MCI) or other known dementia risk factors. Subjects underwent dynamic Aβ-amyloid and vesicular monoamine transporter 2 PET imaging using [(11)C] Pittsburgh compound B (PiB) and [(11)C]dihydrotetrabenazine (DTBZ), respectively, and neuropsychological assessment. PiB and DTBZ PET data were analyzed using the Logan graphical method to determine cerebral PiB deposition relative to the cerebellar hemispheres and striatal DTBZ binding relative to occipital neocortex. Component z scores were calculated for individual cognitive domains (memory, visuospatial processing, working memory/attention, and executive function) and combined linearly for global estimation of cognition. Correlation of cognitive function and cortical PiB binding was investigated.
RESULTS:
Elevated cerebral PiB binding at levels seen in patients with AD was infrequent (6 of 40 subjects). Mean cortical PiB binding in the entire cohort was 1.16 ± 0.16 (distribution volume ratio; range 0.96-1.78). A significant correlation was noted between cortical PiB binding and global composite cognitive function (r = -0.55, p < 0.005) as well as the Wechsler Adult Intelligence Scale score (r = -0.54, p = 0.0004).
CONCLUSION:
Elevated cerebral Aβ-amyloid deposition at levels seen in Alzheimer disease is uncommon in subjects with PD at risk for dementia. In our sample, the prevalence of markedly elevated PiB binding was significantly lower than that found in prior studies of cognitively normal elderly individuals. Neocortical PiB binding correlated robustly with measures of cognitive impairment in our cohort.
PMID:
22933741
[PubMed - indexed for MEDLINE]
PMCID:
PMC3525303
[Available on 2013/9/11]
I am sending to your attention updated information on the matter.
Telomere Length Shortening and Alzheimer Disease—A Mendelian Randomization StudyYiqiang Zhan, MD1; Ci Song, PhD1; Robert Karlsson, PhD1; Annika Tillander, PhD1; Chandra A. Reynolds, PhD2; Nancy L. Pedersen, PhD1; Sara Hägg, PhD1
[+-] Author Affiliations 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
2Department of Psychology, University of California, Riverside
JAMA Neurol. 2015;72(10):1202-1203. doi:10.1001/jamaneurol.2015.1513.
how can the paper be related to AD treatment ? I could read the abstract only [no free access]; best regards, Mauro Colombo
Olfactory testing uses extended to Alzheimer’s disease
Published on November 20, 2015 at 5:15 PM · No Comments
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By Eleanor McDermid, Senior medwireNews Reporter
A simple olfactory test may help to identify people at increased risk of developing Alzheimer’s disease (AD) dementia, suggest findings from a population-based study.
Olfactory dysfunction, already considered a strong risk indicator for Parkinson’s disease, significantly predicted both amnestic mild cognitive impairment (MCI) and further progression to AD dementia among 1430 cognitively normal people aged an average of 79.5 years.
Rosebud Roberts (Mayo Clinic, Rochester, Minnesota, USA) and study co-authors suggest that “odor identification tests may have use for early detection of persons at risk of cognitive outcomes.”
NEW BIOMARKER FOR ALZHEIMER”S diagnosis http://www.news-medical.net/news/20160209/New-discovery-takes-medical-professionals-a-leap-forward-to-effectively-diagnose-Alzheimers-disease.aspx
http://www.news-medical.net/news/20160211/TAU-research-highlights-neuroprotective-potential-of-protein-protectant-drug-candidate-SKIP.aspxActivity-dependent neuroprotective protein (ADNP), essential for brain formation, is frequently mutated in children on the autism spectrum. In older men and women, ADNP expression in the blood is correlated with cognition and further altered in Alzheimer's disease. While the three-to-one ratio of autism in boys to girls is well known, as is the greater number of female Alzheimer's patients than male Alzheimer's patients, the reasons for these phenomena -- and the theory that men and women may have different brain constitutions -- remain in hot dispute.
New research from Tel Aviv University highlights the neuroprotective potential of SKIP, a four-amino-acid peptide ADNP-replacement therapy developed at the university, and the marked difference in the nerve cell communication in male and female mice. If researchers come to understand how ADNP -- an activity-related neuroprotective protein that is a major regulatory gene -- acts differently in males and females, drugs for potential therapeutics can be optimized to treat both autism and Alzheimer's disease.
The research was led by Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU's Sackler Faculty of Medicine and a member of TAU's Adams Super Center for Brain Studies and the Sagol School of Neuroscience. It was recently published in Molecular Psychiatry.
activity-dependent neuroprotective protein (ADNP), the levels of which can be easily monitored in routine blood tests. The study also found that ADNP levels tested in the blood correlate with higher IQ in healthy older adults.A new discovery by Tel Aviv University, Technion (Rambam Medical Center), and Harvard University researchers takes the medical community a leap forward in the process of effectively screening and diagnosing Alzheimer's disease. The new study, published in the Journal of Alzheimer's Disease, proposes a new biomarker for cognitive aging and Alzheimer's disease: activity-dependent neuroprotective protein (ADNP), the levels of which can be easily monitored in routine blood tests. The study also found that ADNP levels tested in the blood correlate with higher IQ in healthy older adults.discovery by Tel Aviv University, Technion (Rambam Medical Center), and Harvard University researchers takes the medical community a leap forward in the process of effectively screening and diagnosing Alzheimer's disease. The new study, published in the A new discovery by Tel Aviv University, Technion (Rambam Medical Center), and Harvard University researchers takes the medical community a leap forward in the process of effectively screening and diagnosing Alzheimer's disease. The new study, published in the Journal of Alzheimer's Disease, proposes a new biomarker for cognitive aging and Alzheimer's disease: activity-dependent neuroprotective protein (ADNP), the levels of which can be easily monitored in routine blood tests. The study also found that ADNP levels tested in the blood correlate with higher IQ in healthy older adults.Medical professionals have to conduct a long series of tests to assess a patient's memory impairment and cognitive skills, functional abilities, and behavioral changes to accurately diagnose Alzheimer's disease. They also have to execute costly brain imagining scans and even, sometimes, invasive cerebral spinal fluid tests to rule out other diseases. The process is laborious at best -- and subjective at worst.
A new discovery by Tel Aviv University, Technion (Rambam Medical Center), and Harvard University researchers takes the medical community a leap forward in the process of effectively screening and diagnosing Alzheimer's disease. The new study, published in the Journal of Alzheimer's Disease, proposes a new biomarker for cognitive aging and Alzheimer's disease: activity-dependent neuroprotective protein (ADNP), the levels of which can be easily monitored in routine blood tests. The study also found that ADNP levels tested in the blood correlate with higher IQ in healthy older adults.
The research was led by Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and former director of the Adams Super Center for Brain Studies at TAU's Sackler Faculty of Medicine and a member of TAU's Sagol School of Neuroscience, conducted by TAU PhD student Anna Malishkevich and spearheaded by Dr. Gad Marshall, Dr. Aaron Schultz, and Prof. Reisa Sperling of Harvard University, and Prof. Judith Aharon-Peretz of Rambam Medical Center - The Technion Institute of Technology.
A step to early intervention
Significant increases in ADNP RNA levels were observed in patients ranging from mild cognitive impairment (MCI) to Alzheimer's dementia. ADNP levels tested in plasma and serum samples, as well as white blood cell RNA levels, distinguished among cognitively normal elderly, MCI, and Alzheimer's dementia participants.
For the purpose of the cross-sectional study, the investigators analyzed blood samples taken from 42 healthy adults, MCI patients, and Alzheimer's disease patients at Rambam Medical Center in Israel. After comparing the ADNP expression in the blood samples, the researchers prepared plasma samples and once again compared the protein levels.
A multicenter study led by Christian Haass and Michael Ewers of Ludwig-Maximilians-Universitaet in Munich has identified a biomarker associated with the activation of an innate immune response to neural damage during early stages of Alzheimer's disease.
I could just download the alleged paper: it is a review process, but freely accessible in PubMed, Mauro C
Regretably there are no such biomarkers - On the other hand there is no efficient treatment either...
When we follow patients in clinic, we use simple bedside tests of cognitive function, such as the MMSE, or the MoCA. From clinical trial work, we know that the rate of decline in most AD patients is about 4 points per year (on average) on the MMSE. The variability from day-to-day on the MMSE is 1-2 points. When we see decline that is greater than 6 points per year, then we send the patient for blood tests (A1c, TSH, B12) and repeat MRI scan, suspecting a silent stroke, or another disease process.
good hint, kind Linda
In my Institute, as simple bedside testing, we use to combine MMSE with clock test, in order to quickly explore complementary cognitive abilities; we recommend the Mendes scoring, which distinguishes visuospatial / attentional / numeric factors [a paper is in my ResearchGate profile].
Best regards, Mauro
Scientists find tau protein as better marker of Alzheimer's disease
A buildup of plaque and dysfunctional proteins in the brain are hallmarks of Alzheimer's disease. While much Alzheimer's research has focused on accumulation of the protein amyloid beta, researchers have begun to pay closer attention to another protein, tau, long associated with this disease but not studied as thoroughly, in part, because scientists only recently have developed effective ways to image tau.
. Mun MJ, Kim JH, Choi JY, Kim MS, Jang WC, Lee JJ, Eun YL, Kwak SJ, Kim KW, Lee SB: Polymorphisms of small ubiquitin-related modifier genes are associated with risk of Alzheimer's disease in Korean: A case-control study. J Neurol Sci; 2016 May 15;364:122-7
[Fulltext service] Download fulltext PDF of this article and others, as many as you want.[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
[Title] Polymorphisms of small ubiquitin-related modifier genes are associated with risk of Alzheimer's disease in Korean: A case-control study.
Sumoylation regulates transcription factor transactivation, protein-protein interactions, and appropriate subcellular localization of certain proteins.
Previous studies have shown that sumoylation of amyloid precursor protein (APP) is associated with decreased levels of amyloid beta (Aβ) proteins, suggesting that sumoylation may play a role in the pathogenesis of Alzheimer's disease (AD).
We investigated the association between polymorphisms of the SUMO genes and the risk of AD.
Our study subjects consisted of 144 AD patients and 335 healthy controls without dementia.
We focused on tagged single nucleotide polymorphisms (tagSNPs) of the SUMO1 and SUMO2 genes.
The tagSNPs were amplified by PCR and sequenced.
We used binary logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the associations between SUMO gene polymorphisms and the risk of AD.
We found that rs12472035 polymorphism of SUMO1 was significantly associated with an increased risk of AD in male group (the CT genotype of rs12472035: adjusted OR=8.737, 95% CI=2.041-37.41, p-value=0.003).
In addition, two polymorphisms of SUMO2 were significantly associated with an increased risk of AD in female group (the GA genotype of rs35271045: adjusted OR=2.879, 95% CI=1.399-5.924, p-value=0.004; and the TC genotype of rs9913676: adjusted OR=2.460, 95% CI=1.197-5.057, p-value=0.014).
Furthermore, three combinations were associated with an increased risk of AD.
Our data suggest that three individual polymorphisms and three combinations may be potential risk factors for AD in Korean population.
However the role of tau protein for primary diagnosis and screening has been proved, but the treatment following up is a serious trouble. Unfortunately, the formation time of recent protein is the main reason that the Alzheimer therapy can’t use it. Therefore, another parameter must be used for this problem.
Genetic risk score may help detect Alzheimer's disease risk in healthy young adults
New research shows that a genetic risk score may detect those at higher risk for Alzheimer's disease long before symptoms appear—even possibly in healthy young adults, according to a study published in the July 6, 2016, online issue of Neurology, the medical journal of the American Academy of Neurology.
New mouse model reveals how Alzheimer's causes dementia
Using a novel, newly developed mouse model that mimics the development of Alzheimer's disease in humans, Johns Hopkins researchers say they have been able to determine that a one-two punch of major biological "insults" must occur in the brain to cause the dementia that is the hallmark of the disease.
A new classification system for biomarkers of Alzheimer's disease that includes measures of amyloid (A), tau (T), and neurodegeneration (N) has been proposed.
The system, described in a paper published online July 1 in Neurology, includes different ways of measuring all three
the paper pointed out by Marianne Levon Shahsuvaryan is freely available in the web: thank you for the hint, Mauro C.
TORONTO — A drug that inhibits tau aggregation significantly reduces disease progression in patients with mild to moderate Alzheimer's disease (AD), but only in those not already receiving standard therapy with AD medications, a new phase 3 study shows.
The study is viewed by some experts as disappointing because it failed to meet its primary endpoint of significantly reducing disease progression in all patients but as positive by others because it informs future directions for this drug.
webmd.ads2.defineAd({id:'ads-pos-520',pos: 520}); "What we have here is a potentially completely new approach to treatment that's based on the tau pathology, which is very closely linked to cognitive decline. What we have shown is that if you attack that pathway, you really do impact disease progression," said study investigator Claude M. Wischik, professor, psychiatric gerontology, University of Aberdeen, United Kingdom.
Dr Wischik is chairman of TauRX Pharmaceuticals, the company developing the new agent — leuco-methylthioninium-bis(hydromethanesulfonate) (LMTX) — a stabilized reduced form of methylthioninium.
An earlier form of the molecule was shown to be effective as monotherapy in a phase 2 trial, with the results presented in 2008 at the Alzheimer's Association International Conference and reported by Medscape Medical News at that time.
The latest findings from the phase 3 trial were presented here at the Alzheimer's Association International Conference (AAIC) 2016.
Primary Endpoint Not Met
The multicenter randomized, double-blind, placebo-controlled study included 891 patients (62% female) with probable AD who had a Mini-Mental State Examination (MMSE) score of 14 to 26, had a Clinical Dementia Rating of 1 to 2, and were younger than age 90 years.
webmd.ads2.defineAd({id:'ads-pos-420',pos: 420}); Participants were recruited at 115 sites across 16 countries in Europe, North America, Asia, and Russia and randomly assigned to one of three study groups: oral LMTX 150 mg/day, LMTX 250 mg/day, or control/placebo LMTX 8 mg/day.
Only 15% of study patients were not taking an AD medication, such as a cholinesterase inhibitor or memantine. The proportion of patients who completed the 15-month trial was 69%.
The trial's primary outcome measure was statistically significant change from baseline on standard measures of cognition and function: the Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores.
Secondary outcomes included assessment every 3 months by MRI of the lateral ventricular volume (LVV) as a disease-modifying outcome, the ADCS-Clinical Global Impression of Change (ADCS-CGIC) and MMSE.
ADAS-Cog and ADCS-ADL assessments were performed at baseline every 13 weeks thereafter. Cranial and MRI scans were performed at baseline/screening and every 13 weeks.
TORONTO ― The University of Pennsylvania Smell Identification Test (UPSIT) has potential as an inexpensive, noninvasive test to help diagnose Alzheimer's disease, a new study shows.
In a study of older adults, both a low score on the UPSIT and positive amyloid beta (Aβ) status predicted memory decline.
webmd.ads2.defineAd({id:'ads-pos-520',pos: 520}); "Reduced ability to identify odors has been seen in patients who are later diagnosed with Alzheimer's disease at autopsy. And decreased odor identification is also seen in those with mild memory symptoms and those who develop Alzheimer's disease dementia," said William Kreisl, MD, from the Taub Institute and Columbia University Medical Center in New York City.
He presented the study at a press briefing here at the Alzheimer's Association International Conference (AAIC) 2016.
an intriguing approach comes - to me - by the concepts of "molecular nexopathies" and of physiological connections.
Here the sentence "In AD, the DMN consistently shows reduced connectivity, and this again corresponds to atrophy patterns in AD and has been shown to predict disease severity and progression 33,34", quoted [page 1236] from Ahmed RM, et al. J Neurol Neurosurg Psychiatry 2016;87:1234–1241. doi:10.1136/jnnp-2014-308350
In the clinic, the severity of AD is best assessed with John Morris' Dementia Rating Scale (CD-R). It takes into account both cognitive performance and functional abilities and can be performed in a short period of time.
Scientists discover gene that may open new door to developing treatments for Alzheimer's diseaseScientists discover gene that may open new door to developing treatments for Alzheimer's disease
Scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have identified a gene that may provide a new starting point for developing treatments for Alzheimer's disease (AD).
Edible and medicinal mushrooms show potential to mitigate neurodegenerative diseasesEdible and medicinal mushrooms show potential to mitigate neurodegenerative diseases
Certain edible and medicinal mushrooms contain bioactive compounds that may enhance nerve growth in the brain and protect against neurotoxic stimuli such as inflammation that contribute to neurodegenerative diseases like dementia and Alzheimer's disease.
Tests that measure the sense of smell may soon become common in neurologists' offices. Scientists have been finding increasing evidence that the sense of smell declines sharply in the early stages of Alzheimer's, and now a new study from the Perelman School of Medicine at the University of Pennsylvania published today in the Journal of Alzheimer's Disease confirms that administering a simple "sniff test" can enhance the accuracy of diagnosing this dreaded disease.
The sniff test also appears to be useful for diagnosing a pre-dementia condition called mild cognitive impairment (MCI), which often progresses to Alzheimer's dementia within a few years.
Neurologists have been eager to find new ways to identify people who are at high risk of Alzheimer's dementia but do not yet show any symptoms. There is a widespread consensus that Alzheimer's medications now under development may not work after dementia has set in.
"There's the exciting possibility here that a decline in the sense of smell can be used to identify people at risk years before they develop dementia," said principal investigator David R. Roalf, PhD, an assistant professor in the department of Psychiatry at Penn.
Roalf and his colleagues used a simple, commercially available test known as the Sniffin' Sticks Odor Identification Test, in which subjects must try to identify 16 different odors. They administered the sniff test, and a standard cognitive test (the Montreal Cognitive Assessment), to 728 elderly people.
The subjects had already been evaluated by doctors at Penn with an array of neurological methods, and according to expert consensus had been placed in one of three categories: "healthy older adult," "mild cognitive impairment," or "Alzheimer's dementia." Roalf and his team used the results from the cognitive test alone, or combined with the sniff test, to see how well they identified subjects in each category.
The increasing use of biomarkers, such as β amyloid and tau, to diagnose Alzheimer's disease (AD) will likely lead to more accurate estimates of the true incidence and prevalence of the disease, concludes a new special report from the Alzheimer's Association (AA).
The report is included in the association's annual "2017 Alzheimer's Disease Facts and Figures" document.
AD biomarkers have the potential to facilitate earlier and more accurate diagnosis and treatment, according to the report, authored by Heather M. Snyder, PhD, senior director, medical & scientific operations, Alzheimer's Association, and colleagues.
A new study published in PLOS Medicine's Special Issue on Dementia has found that the metabolism of omega-3 and omega-6 unsaturated fatty acids in the brain are associated with the progression of Alzheimer's disease.
Study reveals early indication of Alzheimer’s in adults with normal cognition
A new study led by the Keck School of Medicine of University of Southern California (USC) reveals that older adults with elevated levels of brain-clogging plaques, yet normal cognition, experience faster mental decline, suggestive of Alzheimer's disease. The study published in The Journal of the American Medical Association on June 13 presented the earliest precursor—the toxic and sticky protein as part of the disease, before symptoms arise.
dear Marianne, thank you for the hint
yet at a first glance, one more question arises to me: why some people are more resilient than others
High-definition eye scan could reveal crucial warning signs of Alzheimer's disease
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August 17, 2017
Cedars-Sinai neuroscience investigators have found that Alzheimer's disease affects the retina – the back of the eye – similarly to the way it affects the brain. The study also revealed that an investigational, noninvasive eye scan could detect the key signs of Alzheimer's disease years before patients experience symptoms.
Using a high-definition eye scan developed especially for the study, researchers detected the crucial warning signs of Alzheimer's disease: amyloid-beta deposits, a buildup of toxic proteins. The findings represent a major advancement toward identifying people at high risk for the debilitating condition years sooner.
The study, published today in JCI Insight, comes amid a sharp rise in the number of people affected by the disease. Today, more than 5 million Americans have Alzheimer's disease. That number is expected to triple by 2050, according to the Alzheimer's Association.
"The findings suggest that the retina may serve as a reliable source for Alzheimer's disease diagnosis," said the study's senior lead author, Maya Koronyo-Hamaoui, PhD, a principal investigator and associate professor in the departments of Neurosurgery and Biomedical Sciences at Cedars-Sinai.
"One of the major advantages of analyzing the retina is the repeatability, which allows us to monitor patients and potentially the progression of their disease."
Yosef Koronyo, MSc, a research associate in the Department of Neurosurgery and first author on the study, said another key finding from the new study was the discovery of amyloid plaques in previously overlooked peripheral regions of the retina. He noted that the plaque amount in the retina correlated with plaque amount in specific areas of the brain.
"Now we know exactly where to look to find the signs of Alzheimer's disease as early as possible," said Koronyo.
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Keith L. Black, MD, chair of Cedars-Sinai's Department of Neurosurgery and director of the Maxine Dunitz Neurosurgical Institute, who co-led the study, said the findings offer hope for early detection when intervention could be most effective.
"Our hope is that eventually the investigational eye scan will be used as a screening device to detect the disease early enough to intervene and change the course of the disorder with medications and lifestyle changes," said Black.
For decades, the only way to officially diagnose the debilitating condition was to survey and analyze a patient's brain after the patient died. In recent years, physicians have relied on positron emission tomography (PET) scans of the brains of living people to provide evidence of the disease but the technology is expensive and invasive, requiring the patient to be injected with radioactive tracers.
In an effort to find a more cost-effective and less invasive technique, the Cedars-Sinai research team collaborated with investigators at NeuroVision Imaging, Commonwealth Scientific and Industrial Research Organisation, University of Southern California, and UCLA to translate their noninvasive eye screening approach to humans.
The published results are based on a clinical trial conducted on 16 Alzheimer's disease patients who drank a solution that includes curcumin, a natural component of the spice turmeric. The curcumin causes amyloid plaque in the retina to "light up" and be detected by the scan. The patients were then compared to a group of younger, cognitively normal individuals.
Source:
Simple odor identification tests may help track progression of Alzheimer's disease
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August 16, 2017
Odor identification tests may help scientists track the evolution of the disease in persons at risk
By the time you start losing your memory, it`s almost too late. That`s because the damage to your brain associated with Alzheimer's disease (AD) may already have been going on for as long as twenty years. Which is why there is so much scientific interest in finding ways to detect the presence of the disease early on. Scientists now believe that simple odor identification tests may help track the progression of the disease before symptoms actually appear, particularly among those at risk.
"Despite all the research in the area, no effective treatment has yet been found for AD," says Dr. John Breitner, the director of the Centre for Studies on Prevention of Alzheimer's Disease at the Douglas Mental Health Research Centre of McGill University. He is one of the authors of the study on the subject that was recently published in the journal Neurology. "But, if we can delay the onset of symptoms by just five years, we should be able to reduce the prevalence and severity of these symptoms by more than 50%."
Bubble gum or gasoline?
Close to 300 people with an average age of 63 who are at risk of developing AD because they had a parent who had suffered from the disease, were asked to take multiple choice scratch-and-sniff tests to identify scents as varied as bubble gum, gasoline or the smell of a lemon. One hundred of them also volunteered to have regular lumbar punctures to measure the quantities of various AD-related proteins whose presence in the cerebrospinal fluid (CSF).
The researchers found that those with the most difficulty in identifying odors were those in whom other, purely biological indicators of AD, were most evident.
"This is the first time that anyone has been able to show clearly that the loss of the ability to identify smells is correlated with biological markers indicating the advance of the disease," says Marie-Elyse Lafaille-Magnan, a doctoral student at McGill and the first author on the study. "For more than 30 years, scientists have been exploring the connection between memory loss and the difficulty that patients may have in identifying different odors. This makes sense because it's known that the olfactory bulb (involved with the sense of smell) and the entorhinal cortex (involved with memory and naming of odors) are among the first brain structures first to be affected by the disease."
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A cheaper way to track progression of Alzheimer's disease
"This means that a simple smell test may potentially be able to give us information about the progression of the disease that is similar to the much more invasive and expensive tests of the cerebrospinal fluid that are currently being used," the director of research program on Aging, Cognition and Alzheimer's disease of the Douglas Institute and one of the authors on the study. "However, problems identifying smells may be indicative of other medical conditions apart from AD and so should not be substituted for the current tests."
The researchers caution more that far more work needs to be done to see how changes in a person's ability to identify smells over time relates to the progression of the disease itself. For the time being, smell tests are simply one more avenue to explore as researchers look for ways to identify the disease before the symptoms actually begin to appear.
Source:
https://www.mcgill.ca/newsroom/channels/news/could-olfactory-loss-point-alzheimers-disease-269504
kind Marianne,
very interesting inputs
I wondered of the scanty of literature [as far as I know: maybe I mistake] about retinal studying; smelling test is based on sound neurobiological stuff
It may be possible to correlate AD with the macular pigment optical density, MPOD of the entire posterior pole, of the retina. I have discovered such a biomarker.
Dear Barbara Dunning
Hi, Thank you so much for your attention. please explain about your discovery more.
kind Gjumrakch Aliev
just tiried to open the link you posted: it seems not working
best regards, Mauro Colombo
As an physical therapist working in an nursing home , the biomarker is the loss of selectivity that goes faster than by people of the same age without dementia. Using the Senior Fitness Test of Rikli and Jones always was that the most point of differentcy.
warning in the alleged commentary by Lancet is valuable
best regards, Mauro Colombo
Saliva testing of amyloid-β42 (Aβ42) levels may contribute to the prevention of Alzheimer's disease (AD) by determining AD risk and guidance on the use of prophylactic nonsteroidal anti-inflammatory drugs (NSAIDs), new research suggests.
Canadian investigators used a salivary ELISA test to measure Aβ42levels in saliva. They found that elevations in Aβ42 levels in persons at risk for developing AD were similar to levels in individuals who already had AD.
Given that AD is a neuroinflammatory process that begins as early as 10 years prior to the onset of cognitive deficits, the researchers suggest that NSAIDs, initiated a decade prior to the typical age of AD onset, may be effective in staving off these inflammatory effects in people whose Aβ42 concentrations are found to be high.
"We have known since the 1990s that people taking anti-inflammatory drugs are spared from getting AD, but what we didn't know then and know now is how soon before the disease you have to start taking these medications and roughly how much you need," lead author Patrick McGeer, MD, PhD, professor emeritus, Department of Psychiatry, University of British Columbia, Vancouver, Canada, told Medscape Medical News.
"The answers have been very slow in coming, but the knowledge that you can learn a lot from measuring saliva has provided the missing link," he said.
The report was published online March 13 in the Journal of Alzheimer's Disease.
Dear Marianne
Reports on some association of antiinflamatory drugs and prevention of cognitive deterioration do exist in the medical literature for already several decades This rises questions, but as mentioned :
"The answers have been very slow in coming, but the knowledge that you can learn a lot from measuring saliva has provided the missing link," he said.
Regarding that saliva issue - could you please identify by name ', volume, issue and page the article you mention as :
"The report was published online March 13 in the Journal of Alzheimer's Disease. "
Do you know of more reports on this specific issue ?
Thank you
Arthur
Finally, a Winner for Alzheimer's? Anti-amyloid Agent Shows Promise
Pauline Anderson
July 26, 2018
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CHICAGO — Positive results for an anti-amyloid agent in patients with early-stage Alzheimer's disease (AD) is drawing praise, but experts are calling for caution.
Results from the new phase 2 study showed a statistically significant reduction in brain amyloid with a high dose of BAN2401 (Eisai Co. Ltd/Biogen Inc) at 18 months.
In addition, the study showed a dose-dependent, statistically significant, and clinically meaningful slower decline in cognition and function with the highest dose compared to placebo.
"This is the first large clinical trial to support the amyloid hypothesis," Lynn D. Kramer, MD, chief clinical officer and chief medical officer, Neurology Business Group, Eisai Co, Inc, told a press briefing.
The study was released here at the Alzheimer's Association International Conference (AAIC) 2018.
Unique Trial Design
The multicenter study included 856 patients with early AD (mild cognitive impairment due to AD or mild AD dementia) and amyloid pathology confirmed by positron-emission tomography (PET) or cerebral spinal fluid (CSF) tracer.
At baseline, the mean Mini‒Mental State Examination score was 25.6; the mean Clinical Dementia Rating Scale‒Sum of Boxes (CDR-SB) score was 2.9, and the mean Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) score was 22.2.
let's cross fingers
but I modestly invite to caution: too many attemps didn't go further from phase 2 to phase 3 trials, even when the rationale looked strong
best regards, Mauro
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