Alzheimer's Disease - Science topic

To prepare a 0.28 U/ml working solution for an acetylcholinesterase inhibition assay:

Therefore, to prepare a 0.28 U/ml working solution of acetylcholinesterase for the inhibition assay:

Pulses of light and sound seem to have beneficial effects. But some argue it is too soon to market experimental devices...

Ranjan Singh Thank you sir

Hi Swellem,

I was wondering if after staining the brain and washing out the EB dye. Were you able to section your brain and separately stain with some antibody (IF) and see both florophores under the microscope? If so, what wavelength works for EB?

Thanks for your help!

Hi Arisa Furutani

Please go through the following articles discussing in detail how evolution lead to changes in cognition and memory.

1.

2.

Thanks,

Dear all,

I am about to submit for peer-reviewing a methodology for AD-CN classification on a dataset of 36 AD, 29 CN and 23 Frontotemporal dementia patients. I will also make the dataset available at OpenNeuro in the next days, and submit for peer-reviewing a data-article in the following weeks.

I hope that this dataset will suit your research. If so, I would kindly ask you to wait a week or so.

Vahid Rakhshan I will definitely spread the word about this amazing initiative. It's great to know that we can contribute to such a noble cause by simply utilizing our excess computer power. Thank you for bringing this opportunity to my attention. Let's join hands in making a difference in the fight against diseases.

Hi Natalie,

Interesting profile. I think Dr Joy's response is on point and, to follow on from that: The change from the learning trials to delayed memory performance could be captured well perhaps by a process-based measure like the recency ratio.

Also, extra information could be gleaned from the logical memory test

Another question would be whether they are correctly suffering from depressive moods, or whether they have a history of TBI, which I am sure you have already covered.

All best,

Davide

Something like this for action potentials ?

Dear Mostafa Shaban

Many thanks for this. This is really useful!

P.J.

There most likely are many causes of AD.

One prominent theory is loss of autophagy. This dysfunction

allows deposition of tau protein. Rapamycin inhibition of the

mTOR pathway allows improvement in autophagy and repair

of damaged proteins etc.and suggests therapeutic effects.

Mitochondrial dysfunction is also involved. The loss of normal

cell function due to severe mitochondrial damage from various insults

ie ischemia, toxins, hyperglycemia, direct physical damage etc.

Cells die at an advance rate via apoptosis.

I love this topic....so much to learn

Lester Mandelker DVM

Fellow AAVPT

Update: With all the trails and fails: iam still having difficulties with the staining of Tau in my Rats.

May be the chemical iam trying is not inducing tau hyperphosphorylation.

I need to think of new ways until iam 100% sure of it.

Hi. Are you using the Windows version of dcm2niigui? If yes, then this may be your issue.

I suggest you use the Linux (or Mac) version of dcm2nii, or even better is dcm2niix. If you still have problems, then I suggest you use MRtrix3 (specifically the command called mrconvert).

How many dicoms are in the PPMI DTI files? If you know how many volumes there are supposed to be (number of diffusion directions plus number of bzero volumes), and multiply that by the number of slices per volume, then that will equal the total number of slices (dicoms).

Jerome

Please also go through the following RG links.

Before to proceed further, please kindly deeply read the attached book : https://www.springer.com/gp/book/9780387310732

and http://staff.icar.cnr.it/manco/Teaching/2005/datamining/articoli/PRNN.pdf

Hello!

Shaking delivers extra energy to your system - it can shorten the lag time

Best

Please go through the following RG links.

These hypotheses are not mutually exclusive. Already Alzheimer himself has speculated that not the plaques and tangles are the cause of AD, but soluble oligomers of the misfolded Aβ protein. The microscopically visible lesions would then be only correlates, but not cause, of the disease. Perhaps, they could be a waste dump, where afflicted cells put the misfolded proteins in a desperate attempt to reduce the damage done by them. The failure of plaque-reducing antibodies to prevent disease progression could certainly be interpreted that way.

The role of protein modification (spontaneous or enzymatic) in the misfolding and aggregation of proteins in amyloidoses is a very interesting issue, and addresses the pathomechanism one step earlier, but perhaps independently of the question of oligomer/aggregate.

My feeling is that genetic influence is not as strong as some tend to believe. For instance, in cases where we find "the deaf gene", we find almost no offspring that are deaf. In combining my clinical (empirical observations in a case history frame) and objective research experience I find genetics influence but do not determine outcome. Environment added to generic influence is a much stronger and more reliable predictor. In fact, as we begin understanding the plasticity of genes, even within individuals, we see a huge range of generic expression over time---from genetic repair to genetic breakdown. The Methuselah Mouse studies bear this out quite well.

But getting back to the core question of hearing loss---no matter what underlying genetic influence we can today conclude that uncorrected hearing does indeed influence both identifiable cognitive behaviors and the underlying physical cascade that brings it on. It is so pervasive that in one (University of Pittsburgh, 1999) meta-study of 32 studies on Alzheimer's and hearing loss, that older adults that were diagnosed with dementia (Alzheimer's), 92% were found to have uncorrected hearing loss.

The research trail before that (Chartrand, 1990; UT-Austin, 1992; University of South Florida, 1996) was better explained and framed in subsequent studies, such as Brandeis University (2006, 2008, 2012) and John Hopkins (2011, 2012, 2014, 2017)--to name but a smattering of the evidence that dementia and uncorrected hearing loss are, for sure, bosom buddies of the first order. But who's paying attention? The entire clinical community of mental health remains, in my opinion, in blissful denial.

For that reason, I started this project to try to 1) alert my colleagues of this massive and critical oversight, and 2) invite more evidence--pro or con--from anyone wishing to shed more light on the subject. To-date, no one has introduced hard data proving the central theme of this project is in error. I appreciate all of your comments--and hope we do the bold thing by getting the word out, thusly: No mental health assessment of an older adult is valid or conclusive until their hearing acuity has been evaluated and any hearing deficiency corrected. Once that has happened, one may have confidence that the diagnosis is reasonably valid, all other factors being equal. But to treat for dementia without first treating the hearing loss represents, at best, professional and clinical negligence.

Yes, try these two out. With keras you can build deep learning models very fast.

In addition you can try to find even better features.

A hyperparameter optimization could improve your classifier. However, I would try this last. First find good features and a suitable model.

All the best for you.

Hi Santosh Jadhav , I have checked the link that you pointed me out but I need to assess low-molecular weight oligomers that coexisted with Abeta plaques and soluble Abeta40 and 42.

Thanks!

There is a nice article in Nature Neuroscience 2019;22:65-77.... "TDP-43 extracted from FTD brains displays distinct aggregate assemblies and neurotoxic effects."

They showed that FTD-TDP type A patients were more likely to manifest signs of behavioral variant FTD, and that FTD-TDP type B patients were more likely to manifest signs of the motor neuron variant of FTD, while the FTD-TDP type C patients showed signs of semantic dementia.

Hi Claire,

According to my experience pTau in such models is often not as you would expect and comparable to a human AD brain. Typically you should also find hyperphosphorylation of some neurites within neuritic plaques. What could help you is using TrueBlack as a quencher for autofluorescence and then label with MOAB2 + pThr231 Tau [ EPR2488]. This one may be less prone to conformational differences from fixation procedures, and if you are using citrate buffer steaming (if FFPE) you might be able to increase labeling results. pThr231 is typically also found naturally to some extent, so you should also know from WT that the labeling works. Beside that this p Site is early hyperphosphorylated in AD and is typically also one of the first to become positive in amyloid/PS models.

Just as idea,

Good luck,

Daniel

Thank you Priya Prakash, what is the thickness of the mice brain tissue you suggest for CD68 staining? And if they need to be cryostat, microtome or vibratome sections?

As part of our research work in developing machine learning framework for dementia analysis using EEG data, we have made the source code and data (both AD and Controls) publicly accessible. The links are in the acknowledgement section. I hope this will be useful to you.

I would agree with the previously provided answers, however I would inquire about the following: 1st what is the interval between injection of LPS/Control and water maze? 2nd you stated that you have controls, did their injections schedule match? If both Controls and LPS injected mice both display equal amounts of thigmotaxis, it is possible that the injection itself could be the issue not so much the LPS. Mice inherently more stressed and water maze results vary greatly between laboratories. The injections may be the cause of stress can you do the following to reduce the stress of injections: 1) give LPS or Control injections after maze, if it is daily injections or 2) if you could give injections well before testing e.g. 24/48hrs before start of maze. As for exclusion, did you have an a piori parameter for exclusion? If not than no they should not be excluded. A easy test would be to have a single day of visible platform performance after hidden platform and probe testing. Once an a prior exclusion factor is established, such as failing the visible platform test, only those animals can be excluded. As in all animal behavioral testing, consistency is paramount to good data.

There is much less on diet and progression of AD than on diet and the onset of AD. However, here are a couple of recent articles that you may find interesting and

Regards,

Simon Young

Dear Anastasios Mastrokolias,

Look the link, maybe useful.

Regards,

Shafagat

Please check

Susan J. Burke, Heidi M. Batdorf, David H. Burk, Robert C. Noland, Adrianna E. Eder, Matthew S. Boulos, Michael D. Karlstad, J. Jason Collier

J Diabetes Res. 2017; 2017: 8503754. Published online 2017 Sep 6. doi: 10.1155/2017/8503754

Dear Anton

Exclude other metabolic issues like hypothyroidism or encephalopathy due to metabolic errors also mild concussion may cause some psychiatric manifestations including depression which may then mask her cognitive abilities and reserve and appear as if declining cognitively while the fact that she is depressed so is not communicating or refusing to.

Hereditary spastic paraplegia is a heterogeneous group of disorders, the predominant signs and symptoms of which are lower extremity weakness and spasticity. Defects in various pathways (e.g. axon transport, mitochondrial function, myelin formation, ER-stress response, endosomal trafficking, Ubiquitination, etc) have been shown to cause this disorder. However, all HSP subtypes are characterized by corticospinal tract axonal degeneration.

Regarding the age of onset, there is indeed a wide variability between different subtypes and even in one subtype within a family. For instance, a huge variation in the age of onset (6–60 years) has been reported in an Italian family with a mutation in Atlastin (S259F) [Smith, Bradley N., et al. "Four novel SPG3A/atlastin mutations identified in autosomal dominant hereditary spastic paraplegia kindreds with intra‐familial variability in age of onset and complex phenotype." Clinical genetics 75.5 (2009): 485-489].

We certainly need large scale genomic studies in order to make some progress in understanding the underlying pathological mechanisms involved.

You could try to use P2YR12, it is microglia- specific in brain (resting microglia) and the expression in activated microglia is dramatically decreased.

Dear Arturo,

great! Glad to know you are in what seems to be a promissing direction.

All the best in your research.

Luis

Hello Yuka, I think you had quite some input from Aparajita. I'll just try to give you some theoretical background...

As far as I can see you are using a primary Ab raised in mouse on mouse brain. A good perfusion will of course remove most of the blood from the vessels in the brain, still when using mouse primaries you will often have to deal with the natural reactivity of the secondary Abs with the residual mouse Abs in the brain, so unless your primary is very strongly binding to its epitope you'll have to cope with many stripes that light up all over your section.

Second issue is autofluorescence. As already mentioned it is highest in the green and often found also in the red. Still if you have a weak Ab it might not be wise to use a red or far red conjugation, since the photosensors arrays on the modern digital cameras are built dedicating two photodiodes to the green and only one to red and blue, so any emission richer in the green spectrum will result double the intensity than an equal emission in the red or the blue. And confocal microscopy loses so much signal in favor of image clarity and resolution, probably more than 80%, so you need good signal and good detection, as Aparajita already pointed out.

Autofluorescence is given by blood and many other unsaturated or aromatic substances found in the cells, as well as from free(unreacted) aldehydic groups from the fixation, so you do have some chemical treatments, typically via red-ox, to quench them before you start blocking. One possibility is, as described, H2O2. This should reduce at least blood fluorescence. Other possibilities, more specific for reducing aldehydic groups from formaldehyde (bur also sugars and other substances) are 100 mM NH4Cl or 100 mM glycine, 30 min to 1 hr at room temperature. Finally if you need to be really harsh you can use NaBH4, a strong reducing agent for aldehydic, chetonic, carboxylic, and ester groups, that you have to prepare fresh at 1 mg/ml and apply immediately to your sections, 3x20 min (it will fizz evidently, producing gas).

Other issue might be the penetration of your antibody in the thick tissue. For this we use to complement the blocking and the antibody dilution solutions with 1-4% DMSO (depending on the thickness and coarseness of the tissue, in your case 1-2% should be enough). DMSO is technically non-denaturing for proteins, but in substituting water molecules alters slightly their structures due to its greater steric hindrance, producing holes in the thick extracellular matrix and fixed cytoplasm, allowing your Abs to penetrate up to 2-3 layers of cells into the slice. Just a note on the use of 20% DMSO mentioned by Aparajita, seems high, we tried it without particular success on entire embryonic diaphragms and we went back to our standard 2% provided also with the Abs, but I suppose the idea is the same.

Concerning the blocking, you tried already a few things, from very stringent (10% serum) to mild (4% BSA)... if you didn't observe any change, it means that's not your issue: if you lose signal with stringent blocking it means your Ab needs less blocking, if you have too much background with low blocking it's the opposite... sometimes you'll need to look for the compromise. But if you didn't observe differences, then blocking is not an issue for your specific Ab, and you can stay low, or have no blocking.

Last issue are the conditions at which you incubate your Ab. The kinetics and thermodynamics of Abs binding are pretty complex and unpredictable. Three factors can play an important role: pH, temperature and time. Most Abs will work optimally at any pH, but some will prefer pH 8, while others will prefer pH 7.4... if you have problems with a staining, you should try if pH makes a difference. Secondly temperature: typically one incubates Abs O/N at 4 °C. If all works well, fine, if not, try O/N at room temperature instead. Sometimes it also helps 1 hr at 37 °C. And time... although O/N is working most of the times, we have Abs that need 2-5 days, either at 4 °C or at RT to give enough signal for confocal or super-resolution microscopy.

Final point, it sounds a bit odd that a specific mouse line should behave differently form others. I would look more into your procedures. If you only tried on one 5xFAD mouse, it is possible that for example the perfusion was not very successful and you have more blood left in the vessels... Also the plaques, although insoluble aggregates, should not particularly affect a staining (although you didn't tell us what you are staining, if it is in the plaques themselves, in the matrix or in the cells!).

Good luck!

Pietro

Hi Jahnu, you could always do the classical internalization assay using radiolabeled I125, C14 or H3 ligand.

FlowCy and confocal are subjective for quantitatively determining internalization. Using radiolabeled ligands gives you an absolute quantitative value.

I hope you find it useful

Digit Cancellation Test:

Zazzo R. Test des deux barrages. Actualités pédagogiques et psychologiques . Neuchâtel, Switzerland: Delachaux et Nestlé; 1974.

Pattern Comparison Test:

Salthouse TA Babcock RL. Decomposing adult age differences in working memory. Development Psychol . 1991;27:763–776.

Regards

Gongo red is specific for amyloid and easier to do than a silver technique. H&E is all general "stain all(most)" tissue types of technique to give an overview of what is happening. An LFB/CV luxol fast blue counteren with C violet is another good easy CNS stain.

Several studies have identified metals such Pb, Fe, Al, Cu and Zn in AD pathogen sis. Metal ions are known to catalyze the production of free radicals and induce mental retardation or dementia, Since several dietary polyphenols are known to chelate metals, their routine use may also be protective against the onset of AD. For details consult J Alzheimers Dis. 2010 Jan: 19 ( 4 ) : 1123 - 1139

To see neuron/glia in hippocampus, Niissl stain (Cresyl voilet) is the conventional one.

I not am sure I quite understand what you mean by "Alzheimer-formed cell line".

Anyway, APPswe-N2a is neuro-2a cell line stably expressing the human APP Swedish double mutations at codons 670 and 671 of APP-770 in N2a cells. The Swedish mutation is a well-researched, if not the most-researched, Alzheimer's disease mutation. These cell lines are quite popular in the A.D research community and can easily be obtained from numerous scientists all over the world. So, I suggest you look for scientists working with these cell lines in countries around you and make a request from them, I am sure they will be glad to send you some vials because I don't know if these cell lines are commercially available. Good luck!

Finally, a Winner for Alzheimer's? Anti-amyloid Agent Shows Promise

Pauline Anderson

July 26, 2018

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.

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.

Hi,

The journal of biological chemistry (JBC) declares in the editorial recommendations that "Normalize signal intensity to total protein loading (assessed by staining membranes for total protein) whenever possible. “House-keeping” proteins should not be used for normalization without evidence that manipulations do not affect expression.".

For more information the JBC indicates:

Interestingly, Dr Oh informs that journals often openly state that of the western blotting normalization methods they prefer, total protein techniques are at the top of the list. In fact, since 2012 when it was first introduced, stain-free total normalization has appeared in over 800 publications (almost 500 of those appearing in 2017).

For more information

I suggest as total protein quantification method the membrane staining with Ponceau S., Coomassie Blue or Amido black.

Best regards.

Mauricio

Most individuals have targeted the rodent dorsal hippocampus for learning and memory work, since of course the case of H.M., disregarding the sloppy monkey work that quickly followed trying to replicate H.M.'s amnesia. The work picked up again with David Olton's hippocampal disconnection lesion work in the mid-seventies, using the radial-arm maze, fining that the dorsal hippocampal lesion was just as effective as entorhinal and dorsal hippocampal lesions or entire hippocampal lesions. LTP also had its heyday in the dorsal hippocampus,regardless of whether the perforant-path Dentate or CA3 to CA1 pathways were examined. Possibly most relevant is Richard Morris' work of the 80s onward, shifting from hippocampal lesions to intrahippocampal infusion of N-Methyl-D-aspartate (NMDA) receptor antagonists, A-Phosphono-valeric Acid (APV), used to block both LTP and learning. Coordinates from this work in the Wmaze may be the most relevant. Encompasing his J.Neurosci. publications and his slew of Nature papers.

Matching strain and size is important, and Morris' has a J. Neurosci. paper where India Ink was also infused intrahippocampally to catch the spread of the infusion and document it in Histology to show restriction to Hippocampus, as well sufficient spread within the dorsal hippocampus. Others, have used Prussian Blue reactions during histology to passing current through insulated injection cannulae to again mark the infusion sites.The intracerebral infusion work was important with the staining, beaus it permitted separation of mechanical damage from cannulae implantations from that of the infusate.

Thank you Muneeb and Santosh for your suggestions.

Hi Henrique,

We have used the Depression Anxiety Stress Scales (DASS) in quite a few studies and it shows good psychometric properties. Furthermore, it's free and you'll get additional readings (depression and anxiety) in addition to stress. Here is the website from where you can download the scale and obtain additional information. Regards. Rodrigo.

http://www2.psy.unsw.edu.au/dass/

Thanks for the alternative methods and sugestions from James and Taussif. They were very kind and I will try to choose the best that I can do. I will tell you the results. Thanks a lot.

Hi Mona and Muneeb. Thank you so much for your suggestion.

I was wondering if the filaments with microfluids chambers are axon, I could differentiates axon. I took the thick filaments which are at proximity of soma (cell body) as dendrites. So I am confused in the selection appropriate axons. In the image I have attached, soma in not under focus as I scanned the image with prim focus on neurites (axon and dendrites). I have already taken and scanned images for only cell body(soma). That's why I need to distinguish axon in the image I have attached. Your suggestion would be highly appreciable. Thank you once again.

Please note than John Tukey is the correct spelling. I suspect he would turn in his grave knowing that he is referred to as TuRkey, as they are regularly eaten over Thanksgiving!

Back home, they say if someone can't find his car key (forgot where he put it) this will be the first sign.

Hi Nageeb, unfortunately animal models of diseases dictate that they show the full blown pathology within a year if you are looking to get funded.

An animal model of sporadic AZ might be out there, but it will probably not get funded since they are sporadic and non-reproducible unless you have a large cohort of animals.

Dear Dalia,

I hope that those articles will be useful. Best Luck.

ovariectomized females to eliminate the cycle effect?

Please allow me to respond succinctly, since there are still no effective ways of treating Alzheimer's disease. The reason for this situation lies in the lack of specific knowledge about the key mechanisms for the development of this neurodegenerative process. Beta-amyloid and tau-protein disrupt the functioning of neural networks in the brain. Inactive nerve cells begin to die. And most often only at this late stage clinicians diagnose Alzheimer's disease. In recent years, scientific articles have appeared, the authors of which are trying to use stem cells to fill the number of dead neurons. In fact, this is a situation where in this way clinical specialists try to increase the number and potential of "normal" neurons in the brain. But this is basically a palliative approach. It is necessary to find the mechanism of the disease development.

Hi. The glutamate receptors mediate excitatory neurotransmission in the brain and are important in memory acquisition, learning, and some neurodegenerative disorders. This receptor family is classified in three groups: the N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-kainate, and metabotropic receptors.

You answered your question. Yes, external magnetic fields affect MEG recordings and quite easily can make them useless. What MEG measures is extremely weak magnetic field induced from neuronal currents. Background (external) magnetic field is much stronger and it would be probably impossible to measure brain magnetic field if the MEG recording rooms were not magnetically shielded.

Regarding the second question, check out TMS (Transcranial magnetic stimulation).

I am working with risk genes for the obesity, as risk factor of cardiovascular diseases. I used GWAS by traits associated with the obesity, both anthropometric and biochemical. I generated the table with all related studies. Then I was filtering the data. For me it was important to obtain results obtained or validated on Caucasians. After this I understood that an ontology of traits would be necessary to exclude overlappings, e.g. results for 'lipid' trait and 'HDL cholesterol', excluding the one referred to more general trait in the ontology. This gives you one more outcome - you will know which pathways to analyze, so have hints on involved proteins! Then you may turn your attention to the candidate genes, associated genes etc, in order to check what might be missing. And complement ( but dont forget to to mention the source of each gene in your list, might be helpful in some cases). If you have your experimental data, you may try to "validate" them. Or you can check for microarray or RNAseq data, in order to check your gene list there and identify if reliable data are included regarding gene co-expression.

So, it may make your analysis heavier, but still you need a step to prove what you've obtained.

Good luck

Hi,

Currently, International Working Group (IWG) and National Institute on Aging Alzheimer's Association (NIA-AA) has proposed several biomarkers as diagnostic criteria which includes cerebro spinal fluid (CSF) amyloid beta (Aβ) and tau, atrophy on MRI, glucose metabolism on [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and fibrillar Aβ burden on amyloid PET.

There are few regions, which acts as definite Hallmark regions for AD. You could refer to below attached papers.

Structural MRI and Amyloid PET Imaging for Prediction of Conversion to Alzheimer's Disease in Patients with Mild Cognitive Impairment: A Meta-Analysis

Biomarker-based prediction of progression in MCI: Comparison of AD signature and hippocampal volume with spinal fluid amyloid-β and tau

I hope these article will help you.

Further, regarding the medication you could look into these articles

Drugs for Alzheimer’s Disease: Are They Effective?

Gud Luck !!!!

Dear Das,

There is no such recommended algorithm best designed for feature selection task. Rather you will have to test with several of them on your application and check for the best one. However, you may find some real applications of algorithms used recently in feature selection task in the following papers:

1. Suk, H. I., & Shen, D. (2013, September). Deep learning-based feature representation for AD/MCI classification. In International Conference on Medical Image Computing and Computer-Assisted Intervention (pp. 583-590). Springer, Berlin, Heidelberg.

2. Segovia, F., Górriz, J. M., Ramírez, J., Salas-Gonzalez, D., Álvarez, I., López, M., ... & Alzheimer's Disease Neuroimaging Initiative. (2012). A comparative study of feature extraction methods for the diagnosis of Alzheimer's disease using the ADNI database. Neurocomputing, 75(1), 64-71.

3. Liu, M., Zhang, D., Shen, D., & Alzheimer's Disease Neuroimaging Initiative. (2012). Ensemble sparse classification of Alzheimer's disease. NeuroImage, 60(2), 1106-1116.

4. Shi, J., Zheng, X., Li, Y., Zhang, Q., & Ying, S. (2018). Multimodal neuroimaging feature learning with multimodal stacked deep polynomial networks for diagnosis of Alzheimer's disease. IEEE journal of biomedical and health informatics, 22(1), 173-183.

5. Liu, X., Chen, K., Wu, T., Weidman, D., Lure, F., & Li, J. (2018). Use of multi-modality imaging and artificial intelligence for diagnosis and prognosis of early stages of alzheimer's disease. Translational Research.

6. Zhang, D., Huang, J., Jie, B., Du, J., Tu, L., & Liu, M. (2018). Ordinal Pattern: A New Descriptor for Brain Connectivity Networks. IEEE Transactions on Medical Imaging.

To add to the message from Frederic above, the National High Magnetic Field lab, is free of charge if you intend to publish your results. We have some of the best NMR instruments in the world.

Irrespective on the compound the dose is usually less than 10 mg/Kg. Then I woulg suggest to use 10. If you get not results you may go to 20 but honestly doing to 50 and seeing "somehting" may be just unspecific. Is it possible to use big doses to "cure" disease, sure but better if one finds a compound efficacious at a low dose.

Thank you very much for your great advice, Aderemi! I really appreciate it.

-Xiao

Thank you dear Susana Rivera-Mancía. Your response was so helpful.

Hi Muhammad,

Thanks for your question, certainly a clinical conundrum encountered increasingly frequently and one for which direct evidence is limited. However, a nice review I read recently summarises this well, particularly the impact that NOAC profiles have on the risk:benefit decision you nicely present:

This article provides a very telling conclusion:

"The literature suggests that elderly adults with AF—even those with high bleeding risk—benefit from anticoagulation. The benefit of anticoagulation appears to be most marked in those with high stroke and bleeding risk, a category into which many elderly adults fall. By reducing the risk of ICH, the DOACs may tip this risk:benefit ratio even further toward anticoagulation."

Hope this helps.

Hi Loretta,

Visit this website: https://www.alzforum.org/

Go to Database tab and select Alzgene and press SEARCH THE ALZGENE DATABASE .

Good luck!

Training after inducing Alzheimer is to see what possible can counteract it. Cf. our study:

Hi,

You might want to consider using the Mouse Neuro2a (N2a) neuroblastoma cells stably overexpressing the human Swedish mutant (K670N, M671L) APP (N2aAPPsw, clone Swe.10). This is available as a gift (I think) from Dr G. Thinakaran (The University of Chicago, IL, USA).

Good luck.

Aderemi.

Hello Agrawal,

I agree Sabine Strehl about isolation of phospho protein issue. And I'd suggest you to

Also, just for an idea, maybe phosphorylation affect of protein during transfer. So you can try optimize the transfer time. And lastly, if you have materials you can do immunoprecipitation. I hope you can solve problem.

Good luck!

Hi Etienne!

Here you have many references about studies on ApoE4 in Latin America.

Hope you find it useful!

Best

Josefina

Thank you dear Dulce and dear Bobbi, your Answers were so helpful.

Dear Maria,

We recently published a paper addressing the learning potential of older healthy adults in a university context. Our paper covers mean performance across a range of undergraduate courses, and takes a multi-domain approach to investigating predictors of this educational performance. If this sounds of interest, you can find the publication on my RG profile.

Best of luck with your research.

David.

Hi there,

I'm sure that there are a lot of possible approaches to screen peptide libraries for peptides that prevent A-beta aggregation in-vitro.

However, in contrast to small molecule inhibitors, the main issue with peptides will be the delivery: It will probably not be easy for your peptides to cross the blood-brain-barrier and get into the central nervous system.

Another important aspect is the in-vivo stability of your peptides. If they are unstable and rapidly degraded in-vivo, they will not be very useful. At the same time, you want to make sure your peptides cannot oligomerize or aggregate.

You will find a bit about analytical methods for the characterization of therapeutic peptides here:

Best,

Sebastian

yes thank you

A small percentage of people with Alzheimer’s disease (less than 1 percent) have an early-onset type associated with genetic mutations. Individuals who have these genetic mutations are guaranteed to develop the disease. An ongoing clinical trial conducted by the Dominantly Inherited Alzheimer Network (DIAN), is testing whether antibodies to beta-amyloid can reduce the accumulation of beta-amyloid plaque in the brains of people with such genetic mutations and thereby reduce, delay or prevent symptoms. Participants in the trial are receiving antibodies (or placebo) before they develop symptoms, and the development of beta-amyloid plaques is being monitored by brain scans and other tests.

Another clinical trial, known as the A4 trial (Anti-Amyloid Treatment in Asymptomatic Alzheimer’s), is testing whether antibodies to beta-amyloid can reduce the risk of Alzheimer’s disease in older people (ages 65 to 85) at high risk for the disease. The A4 trial is being conducted by the Alzheimer’s Disease Cooperative Study.

Aducanumab has been tested in patients who had Abeta accumulation in their brains (as per the PET scan), only. Also, the patients were in the very early stages of the disease i.e. few or no memory deficits.

This is important because anti Abeta antibodies aim at decreasing the levels of Abeta. They do not intend to rebuild the already dead neurons. In other studies involving solanezumab, etc. the patients expressed extreme neurodegenration.

In the study with aducanumab, giving the antibody at an early stage to patients who had Abeta in their brain but who still had most of their brain intact is the key differentiator from previous studies.

The difference lies in the study design.

Aluminium hydroxide induced (i.p.) AD is a common and effective rodent model. You can refer to literature for the specific dose.

The WFSBP does not recommend antipsychotic drugs in dementia. There are numerous studies on risperidone, haloperidol and others demonstrating the side effect spectrum. Besides increased mortality extrapyramidal syndroms reduce mobility and increase the number of falls. Becomming unable to move increases the rate of pneumonia and other infections. Many other side-effects are known.

Most of the research groups working in this field can be found in the ISTAART professional interest area under neuropsychiatric syndroms.

hello rita,

i am also working with beta secretase inhibition , did you find your answer?

As per my knowledge sigma has BACE FRET Kit, but they have not given any information on the concentration and volume of drug/ compound that should be used in the assay. If you have some insights?

Dear Higor Iha,

Yes, you are correct...Taconic and Charles River are offering only mice models of AD.