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  • Reply to: Alzheimer’s Disease and Spirochetosis: A Causal Relationship   2 weeks 7 hours ago

    Herbert B. Allen, MD and Erum Ilyas MD, Drexel University College of Medicine, Department of Dermatology

    Dr. McCully mentions that homocysteine is a risk factor for Alzheimer’s disease (AD); and, further, it has been shown to be a risk factor for arteriosclerotic heart disease. Homocysteine has been observed to encourage organisms to “make” biofilms [1]. Inasmuch as we have found biofilms in the plaques of arteriosclerosis [2], and, we and others have also found them in AD, it seems plausible to implicate the biofilm-forming effect of homocysteine in both the worsening of AD and in arteriosclerosis. This is similar to the effect of diabetes on AD where the hyperosmolality in diabetes leads to the creation of more biofilms, and that leads to deterioration in AD [3].

    Drs. Singhrao, Balin, and Poster mention other organisms (in addition to spirochetes) in AD. Again, considered in the light of microbes making biofilms, it has been well documented that biofilms of one species have receptors for organisms of other species (and vice versa). This allows many different organisms to take up residence in the biofilm [4]. The biofilm, in this instance, is more comparable to a “hotel” than a “single family home”.

    References
    [1] Belval SC, Gal L, Margiewes S, Garmyn D, Piveteau P, Guzzo J (2006) Assessment of the roles of LuxS, S-Ribosyl Homocysteine, and Autoinducer 2 in cell attachment during biofilm formation by Listeria monocytogenes EGF-e. Appl Environ Microbiol 72, 2644-2650.
    [2] Allen HB, Boles J, Morales D, Ballal S, Joshi SG (2016) Arteriosclerosis: the novel finding of biofilms and innate immune system activity within the plaques. J Med Surg Pathol 1, 135.
    [3] Allen HB, Husienzad L Joshi SG (2016) Letter-to-the-Editor: The impact of diabetes on Alzheimer’s disease. J Alzheimers Dis, http://www.j-alz.com/content/impact-diabetes-alzheimers-disease.
    [4] Rickard AH, Gilbert P, High NJ, Kolenbrander PE, Handley PS (2003) Bacterial coaggregation: an integral process in the development of multi-species biofilms. Trends Microbiol 11, 94-100.

  • Reply to: What is wrong with Alzheimer’s disease clinical research?   2 weeks 3 days ago

    Comment by Sally Hunter and Carol Brayne

    Given the recent failure of the solanezumab clinical trials, it is understandable that discussions relating to the current state of Alzheimer disease (AD) research focus on the failure of the amyloid cascade hypothesis (ACH) and to a lesser extent the presenilin (PS) hypothesis (PSH). For decades the ACH and to a lesser extent the PSH have driven research with the amyloid beta protein (Aβ), proposed as neurotoxic and causal, as the measure of outcome for experimental design. However, there is a third relevant yet almost completely neglected hypothesis, the amyloid precursor protein (APP) matrix approach (AMA) [1-5] that takes a systems biology approach. This hypothesis suggests an opposing view to the ACH, is compatible with a modified PSH, and addresses long standing concerns relating to complexity within the APP proteolytic system.

    The AMA starts with the suggestion that APP is a hub [6] and describes how the balance of flow through the various cleavage pathways represents a dynamic and iterative system that receives biological information representing the current state of the cell via regulation of the various cleavages and outputs the integrated biological information via the ratios of its proteolytic fragments. This system can respond to wider changes in the cell by changing the relative proportions of the proteolytic fragments released. Several features support this proposal, APP is constantly expressed, has a short half-life of between 1-4 hours, APP concentration is rate limiting and as a result its multiple cleavages compete. This view predicts that as flow through the β pathway increases, flow through the α pathway (and others) is reduced. Expanding this view, we see that any change in flow through the APP proteolytic system involves both gain and loss in equal measure. Therefore we can never be sure that the physiological changes that we see in experimental systems where Aβ expression is increased are due solely to Aβ – loss of full length APP, loss of the N-terminal sAPPα and P3 from reduced α-cleavage or the loss of sAPPβ’ and Aβ’ from β’ cleavage confounds this interpretation.

    In contrast to both the ACH and PSH, which aim to explain the available evidence in relation to the roles of Aβ in AD, the AMA aims to explain the evidence in relation to the behaviour of the entire proteolytic system in both normal and disease states and requires that all the proteolytic fragments are measured. The AMA predicts that the relative ratios of all the fragments are required to describe the state of the APP proteolytic system. This is a major departure from current experimental designs where no study to date has systematically measured these fragments. Exploring this interpretation leads to the conclusion that the confounding effects of all the other proteolytic fragments potentially undermine all current research. An examination of the cross-reactivities of commonly used antibodies illustrates this view [7]. The updated neuropathological diagnostic protocols have suggested that since the monoclonal antibody 4G8 reveals more Aβ pathology it should be the standard antibody used in routine neuropathological diagnosis. However it is not clear where this additional sensitivity comes from or what it represents. This increased reactivity may be due to cross reactivity with P3, the fragment arising from sequential α and γ cleavages, and also cross-reactivity with various catabolic fragments. Further confounding is introduced by the complex molecular behaviours of Aβ and P3 - there is no panel of antibodies that can distinguish between P3 and Aβ across all aggregations states, (monomers, dimers, oligomers and fibrils), across all sequence variations and across solubilities. How then do we best interpret any signal from this or any antibody?

    Unlike the ACH or PSH which focus narrowly on evidence relating to β and γ cleavages and interprets evidence from other cellular systems as secondary or as a consequence of these cleavages, the AMA allows evidence from wider cellular systems to drive APP cleavage. Therefore there is no overarching “causal feature” and various factors such as synaptic activity, immune signalling, metabolism cholesterol etc. can be both drivers of and be driven by APP cleavage through complex regulatory feedback. The coherent behaviour of the APP proteolytic system and its regulatory factors can be understood as contributing to a homeostatic point that allows proper cellular function and in the case of neurons, supports appropriate synaptic plasticity. With ageing, the AMA suggests that the APP system becomes increasingly decoherent so that changes in, say, immune signalling or energy metabolism etc. can stress the homeostatic point beyond that which allows full integration of the biological information. Ageing and cellular senescence programs may alter the homeostatic point to which cellular systems cohere [1].  This re-programming of the homeostatic point has relevance to therapeutic approaches that aim to reduce Aβ. According to the AMA, loss of physiologically relevant Aβ may increase flow through β pathways to replace the Aβ removed so that no long term change would be expected and further, flow through the other APP cleavages would be reduced while this adjustment is in progress with further loss of function from other cleavage fragments.

    The AMA predicts that each mutation in APP and PS can be understood as altering the homeostatic point or the behaviour of the APP proteolytic system as a whole, allowing changes that happen with e.g. age to impact at an earlier age/stage. Each mutation has the potential to alter the homeostatic balance in this system in subtly different ways. If we take this interpretation further, the AMA predicts that multiple disease pathways are possible, each with different drivers and that those arising from mutations do not necessarily relate to those arising through ageing. Further, the AMA suggests that a detailed investigation of each mutation in relation to neuropathology and cognitive status from a natural history perspective will help clarify how the entire system works – an approach that has not yet been acknowledged as useful.

    Because the AMA predicts multiple disease pathways, it also suggests that, unlike familial AD where the presence of a disease associated mutation is a qualitative diagnostic feature, defining sporadic AD as a single disease process in the older population is not possible. Therefore from the perspective of the AMA, there is no way to accurately select sporadic AD cases and controls in randomised controlled trials (RCTs) and any attempt to do so will result in confounding and/or bias.

    It is understandable that the wider research community has not fully engaged with the AMA. The AMA was first described in 2005 in a Master’s thesis for the Open University, UK. It was first submitted to a journal in 2006 where it was rejected without peer review. There followed a cycle of re-write, update, resubmit and rejection without peer review until 2012 – journal editors thus denied the AD research community an alternative framework for many years. When work based on the AMA actually gets to peer review, the perspective of the dominant ACH leads invariably to rejection – again blocking access for the wider research community to this alternative perspective. It is possible that other approaches have similarly had major challenges in being visible to the scientific community. There is a reluctance to engage in a constructive way with avenues outside the role of Aβ, including hypotheses relating to the roles of vascular change, the immune system, metabolic regulation, metal homeostasis and oxidative stress etc. in the evolution of dementia.

    In terms of strategy in the immediate future, the AMA is clear.

    1) In order to fully account for and understand the potentially confounded nature of AD research, we need to accurately describe the APP proteolytic system as a synergistic whole in humans. This will allow us to characterise experimental models in relation to the human so that we can better assess which experimental models of disease are appropriate. Currently this approach is entirely missing from AD research strategy.

    2) Experimental techniques to accurately and reliably measure all the proteolytic fragments need to be developed and validated – not a straightforward task given the complexity of the APP system.

    3) Since the AMA predicts that rate and timing of APP cleavage is as important as any cleavage products, experimental techniques to accurately and reliably measure protein-protein interactions, affinities and rates of reaction need to be developed, standardised and validated.

    4) We need population approaches to generate reliable evidence that describes the APP proteolytic system in ‘normal’ and ‘disease’ states and how this system interacts with wider cellular systems with a view to better defining possible disease pathways in the older population. We may then be able to better select cases/controls for RCTs that reduce confounding and bias.

    5) We need to investigate in detail how wider cellular systems interact with the regulation of APP cleavage so that contributions from important hypotheses that have been relatively ignored relating to cellular systems such as energy and metabolism, oxidative stress, immune signalling, calcium regulation etc. can be understood in both familial and sporadic disease.

    6) Evidence relating to familial AD arising from mutations requires re-interpretation. Subtle differences arising from each mutation have the potential to increase our understanding of the APP proteolytic system as a whole and crucially, this evidence can be reliably interpreted as relating to an AD pathway since the presence of a fully penetrant mutation is a qualitative diagnostic feature.

    Simultaneously following the above recommendations will enable us to better understand the complex problems presented by AD and move towards a rational identification of therapeutic targets. From the perspective of the AMA, we haven’t even started to describe the problem, never mind developing therapeutic solutions.

    References
    [1] Hunter S, Arendt T, Brayne C. The Senescence Hypothesis of Disease Progression in Alzheimer Disease: an Integrated Matrix of Disease Pathways for FAD and SAD. Mol Neurobiol 2013.
    [2] Hunter S, Brayne C. Relationships between the amyloid precursor protein and its various proteolytic fragments and neuronal systems. Alzheimers Res Ther 2012;4:10.
    [3] Hunter S, Friedland RP, Brayne C. Time for a change in the research paradigm for Alzheimer's disease: the value of a chaotic matrix modeling approach. CNS Neurosci Ther 2010;16:254-62.
    [4] Hunter S, Martin S, Brayne C. The APP Proteolytic System and Its Interactions with Dynamic Networks in Alzheimer's Disease. Methods Mol Biol 2016;1303:71-99.
    [5] Hunter S, Brayne C. Integrating Data for Modeling Biological Complexity. In: Kasabov N, editor. Springer Handbook of Bio-/Neuro-informatics. Berlin Heidelberg: Springer-Verlag, 2014. p. 921-40.
    [6] Turner PR, O'Connor K, Tate WP, Abraham WC. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 2003;70:1-32.
    [7] Hunter S, Brayne C. Do anti-amyloid beta protein antibody cross reactivities confound Alzheimer disease research? Journal of negative results in biomedicine 2017;16:1.

     

  • Reply to: What is wrong with Alzheimer’s disease clinical research?   2 weeks 4 days ago

    Jack de la Torre's has written an insightful article on the inability, or unwillingness, of researchers in the field of Alzheimer's disease to determine if a target of interest is truly causative of the disease. Specifically as this relates to the beta amyloid hypothesis. Unfortunately, I think this inability to test one's target-hypothesis can be generalized across the CNS neurodegenerative research space, where we presently have only symptomatic therapeutic relief for any of the chronic neurodegenerative indications. What if, in fact, our early conclusion, "that either we find a means to curb further neurodegeneration by means of a neuroprotective agent, or that we must stop the disease prior to disease onset" is omitting another therapeutic strategy that could, for the first time, reverse disease? We have known for over a decade that the adult brain can indeed produce new neurons and seemingly initiate this process in response to neurodegeneration. So the third option would take advantage of the ability by the brain to self-regenerate, however insufficient under chronic neurodegenerative conditions, and push this process in a (i) disease, and (ii) region-specific and (iii) temporal way.

    Indeed, this has been Neuronascent's view point all along, in that we take advantage of the highly regulated process of new neuron formation, in select regions of the adult brain, to replace dying and lost neurons in aging and neurodegenerative disorders, i.e. endogeneous regeneration. We are not suggesting returning to the idea of growth factor injections, with the many systemic issues that this often causes. The ideal process-stimulation point should be downstream of growth factors, hormones and other initiators of cellular events. We are also not suggesting administration of general mitogens, that would not qualify as either region-specific or working in a temporal way (i.e. timed to the occurrence of neuronal loss). Instead, the aim should be toward selective therapeutics, that first push neuronal progenitors to not only proliferate (i.e. neurogenesis), but to secondly push the migration and differentiation and thirdly the maturation of neurons -- leading to an associated reversal of behavioral impairment in chronic neurodegenerative disorders. It is time to test a completely new hypothesis, not one based on a single target for neuroprotection in these very complex neuron-dying diseases, like Alzheimer's and Parkinson's disease. The hypothesis to be tested looks at the possibility to pharmacologically push the brain in a safe and non-invasive manner to regenerate itself. This hypothesis could even bring back the possibility of a disease-modifying therapy for Alzheimer's disease patients. It is time to invest in such a paradigm-shift. This is not an issue of a "potential" therapeutic discovery program, years away from human testing. Neuronascent, Inc. already has a patented, neuron regenerative NCE, manufactured for the clinic, that has shown to be safe and which could potentially enter the clinic in 2017.

    Judith Kelleher-Andersson, Ph.D., is President and CEO of Neuronascent, Inc. and is the inventor on all of Neuronascent’s technologies.

  • Reply to: Alzheimer’s Disease and Spirochetosis: A Causal Relationship   2 weeks 4 days ago

    Dr. Miklossy takes the clear lead when it comes to linking Alzheimer's disease and infection. It is critical that she and researchers like Dr. de la Torre and Balin continue their fine work. Others should indeed take the baton and drive this research forward. But the question becomes why more research? Yes, we need more research - but we desperately need more "translators" like Dr. Clement Trempe who, for decades has been testing glaucoma and dementia patients for infection and the underlying reason why these individuals have become vulnerable to the proliferation of pathogens in their systems leading to inflammation and neuroinflammation - then to brain-impacting diseases.

    Dr. Trempe "does no harm" in treating his patients. Again, yes, research must continue and that is the job of researchers – that’s what the do. But doctors must not be afraid of the consequences (lawyers) of treating patients well even if it goes against the conventional wisdom or standard of care. There is simply not enough knowledgeable physicians willing to go the extra mile for their patients.

    And you can successfully treat Alzheimer's, dementias, cognitive impairment and glaucoma without treating these diseases by name! It's simple, perform and in depth, broad and deep differential diagnosis and find those diagnostic "suspects" like poor gut health, mold, toxicity, spirochetes, and other pathogens. Once found, treat for them and see your patients get better. What is wrong with this model?

    Yes, we must have brilliant people like Dr. Miklossy doing more research. It a requirement of the doubting clinicians and all the entrenchment surrounding medicine. But we see responses like "need to do more research" end the end of too many research articles because there are NOT ENOUGH audacious clinicians willing to go beyond their comfort zone and try something new.

    Thank God the high tech industry doesn't use the same discovery/develop principles of medicine or we would all still be using an abacus!

    (Anticipating the comments from researchers and scared doctors: What Dr. Trempe and functional doctors do is NO HARM first. It is much more harmful and UNETHICAL NOT to treat a disease that has addressable and treatable causes. Doctors – test for spirochetes and other pathogens. Dare to prescribe vitamin D and cod liver oil – and appropriate anti-infectives – your patients will thank you.)

  • Reply to: Alzheimer’s Disease and Spirochetosis: A Causal Relationship   3 weeks 4 hours ago

    Dr. Miklossy’s blog post documents historical findings that cumulatively suggest spirochete involvement in the development of AD, a hypothesis that urgently requires further study. Indeed, recent findings that the function of Ab peptides may be antimicrobial [1] and neuroprotective against brain infections [2] provide the rationale for further study in this field. Additionally, the development and functioning of the central nervous system may be heavily influenced by gut microbiota [3]. Approximately 10-20% of Lyme disease patients suffer from long-term health deficits that can include neurological sequelae [4,5], suggesting persistent infection and/or indirect immunologically-mediated neuropathology. We agree that well-controlled, rigorous studies will provide much-needed insight to examine a potential role of spirochete infection in AD development.

    Mayla Hsu, PhD. Global Lyme Alliance, Greenwich, CT. http://www.globallymealliance.org 

    [1] Spitzer P, Condic M, Herrmann M, Oberstein TJ, Scharin-Mehlmann M, Gilbert DF, Friedrich O, Gromer T, Kornhuber J, Lang R, Maler JM. (2016) Amyloidogenic amyloid-b-peptide variants induce microbial agglutination and exert antimicrobial activity. Sci Rep 6:32228. Doi: 10.1038/srep32228.

     

    [2] Kumar DKV, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD. (2017) Amyloid-b peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med 8(340):340ra72. Doi:10.1126/scitranslmed.aaf1059.

     

    [3] Sharon G, Sampson TR, Geschwind DH, Mazmanian SK. (2016) The central nervous system and the gut microbiome. Cell 167:915-932. Doi:10.1016/j.cell.2016.10.027.

     

    [4] Aucott JN. (2015) Posttreatment Lyme disease syndrome. Inf Dis Clin N Am 29:309-323.

     

    [5] Cairns V, Godwin J. (2005) Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms. Int J Epidemiol 34:1340-5.

     

  • Reply to: Alzheimer’s Disease and Spirochetosis: A Causal Relationship   3 weeks 3 days ago

    Judith Miklossy should be commended for her continual efforts to bring long overdue attention to potential infectious causation of Alzheimer disease (AD). For the past 3 decades, as she has noted in her blog, reports have highlighted many different types of infectious agents associated with AD; many of these reports have identified direct brain infection and others systemic infection associated with disease [1-9]. In addition, polymicrobial involvement may be likely in many cases. Dr. Miklossy has laid out arguments as to why spirochetes including Borrelia and oral treponemes should be highly considered as causative agents for the development of the pathology as well as the symptomatology found in AD.  She has noted the nature of the filamentous pathology as it relates to both amyloids from both bacteria and eukaryotic cells and suggests that the curly fibers represent individual spirochetal forms while plaques represent spirochetal colonies.  This interpretation may have great importance for understanding the involvement of numerous infectious agents in the CNS as potentially the infectious morphologic forms could actually mimic the eukaryotic fibrils of amyloid and/or actually interact with eukaryotic beta amyloid.  Dr. Miklossy notes the possibility of amyloid from bacteria and eukaryotic cells may very well interact leading to amyloid deposition in AD. She also notes that spirochetes have been shown to induce AD-type lesions with increased APP, Aβ, and phosphorylated tau levels observed in vitro in primary mammalian neuronal and glial cells and organotypic cultures [10].

     

    Historical and current evidence suggests that infection is associated with AD, and while association isn’t necessarily causation, we cannot dismiss this hypothesis without thorough investigation. For far too long, research in the AD field has focused on the pathological hallmarks of disease without considering “triggering events or insults” that actually start the pathogenic process. These events could very well be the interplay of infection along with other genetic and environmental factors. Intriguingly, infection may be involved with both forms of AD, possibly accelerating familial disease to arise in the 4th and 5th decades, and more slowly triggering the late-onset sporadic form of disease in the 6th decade and above. But how do we prove these occurrences?

     

    Studies are needed to test both hypotheses given the high likelihood that infection may enter the nervous system as a primary infection but also as a secondary process following from the development of pathology due to prior damage.  Many of us believe (with evidence - see [3,4]) that direct primary infection could occur through the olfactory neuroepithelia as olfaction deficits arise early in the disease and innervation is direct from the olfactory bulbs into the lateral entorhinal cortex. As this region of the brain is affected very early in AD, infections using this route of entry into the brain (to circumvent the blood brain barrier) such as infection with Chlamydia pneumoniae, Herpes Simplex Virus 1 and possibly others including treponemes, could actually initiate inflammation, amyloid generation, synaptic damage, etc that could start AD pathogenesis. Secondarily, blood brain barrier insult could occur in the same region shortly after as there would be specific signaling from the entorhinal cortex. This could then lead to other insult that may involve systemic factors including other blood-borne infections as well as other chronic conditions predisposing to AD such as atherosclerosis, diabetes and traumatic brain injury. This scenario would certainly account for many of the associated findings in AD in contrast to the more conservative views often citing more conventional understanding of the individual conditions and diseases considered as risks for AD.    

     

    Finally, I could not agree more with Dr. Miklossy that much more attention and support is required for this field of study. A focus on biological underpinnings of disease based on infection gives us many more biomarkers and targets for which we can attempt prevention and treatment. While most of us in this area of research realize much still needs to be accomplished in understanding the infection biology of AD, we cannot wait for the exhaustive clinical trial failures based on other hypotheses before something is done; we cannot continue to spend hundreds of millions of dollars in those futile approaches. We need to act now, and differently, as the lives of so many are in the balance!

     

    1. Miklossy J (1993) Alzheimer’s disease - A spirochetosis? Neuroreport 4, 841-848. 

    2. MacDonald AB, Miranda JM (1987) Concurrent neocortical borreliosis and Alzheimer’s disease. Hum Pathol 18, 759–761.

    3. Balin BJ, Gerard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, Whittum-Hudson JA, Hudson AP (1998) Identification  localization of Chlamydia pneumoniae in the Alzheimer’s brain. Med Microbiol Immunol 187, 23-42. 

    4. Little CS, Joyce TA, Hammond CJ, Matta H, Cahn D, Appelt DM, Balin BJ (2014) Detection of bacterial antigens and Alzheimer’s disease-like pathology in the central nervous system of BALB/c mice following intranasal infection with a laboratory isolate of Chlamydia pneumoniae. Front Aging Neurosci 5, 304. 

    5. Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S (2013) Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J Alzheimers Dis 36, 665-677

    6. Kornhuber HH (1995) Chronic anaerobic cortical infection in Alzheimer’s disease: Propionibacterium acnes. Neurol Psych Brain Res 3, 177-182.

    7. Malaguarnera M, Bella R, Alagona G, Ferri R, Carnemolla A, Pennisi G (2004) Helicobacter pylori and Alzheimer's disease: a possible link. Eur J Intern Med 15, 381-386.

    8. Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF (1991) Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol 33, 224–227.

    9. Pisa D, Alonso R, Juarranz A, Rábano A, Carrasco L (2015) Direct visualization of fungal infection in brains from patients with Alzheimer's disease. J Alzheimers Dis 43, 613-624

    10. Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, Reiss K, Darbinian N, Darekar P, Mihaly L, Khalili K (2006) Beta-amyloid     deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging 27, 228-236.