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Neurodegeneration, The inflammation link ‘The Body from the Brain's Perspective * Inflammation leads to functional changes inthe body's signaling system that increase inflammatory mediators and cut ‘across many disparate diseases as Pl Kevin Spelman, RH(AHG), MCPP Chai - Clinical Dion “Tai Sophia Instituto eee ee eee A Common Etiology Inflammatory conditions are Inflammation explains why epidemiological evidence associates the use of specific ant-inflammatories over periods of time with lowered incidence of certain degenerative diseases in age, such as ‘neurodegeneration or cardiac-related ‘dysfunction Spbiaeaets aaa involved in nearly all chronic, 180 degenerative, age-related pe diseases ~ Secondary signs of diabetes Corporate Awareness! " Corporate Awareness! Neurodegeneration “tis clear, though, that inflammation has moved to center stage in neurodegeneration...” Robert Sapolsky The Web of Physiology ‘er Preeti main sansa eg A ‘naa ea Some anatomists have advocated rewriting textbooks that treat the The Web ‘neuropeptide receptors occur on mobile ‘cells of the immune system; monocytes ‘can chemotax to numerous neuropeptides. Neuropeptides and their ‘eceptors thus join the brain, glands, immune a systems a aan oa neuroimmunoiogy as a single competion Brain! boxy, interacting system ae 9 the biochem The Web oir Wong 188. Ma Pena 86831727 interleukin-1B and IL-1 receptor antagonist appear to play a role in the biology of major depression Proinflammatory Cytokines eta fr eee oe Sinn Jiao a a * Its now generally accepted that inflammatory mediators, including la-derived cytokines such ‘ [L-1b and reactive oxygen species such as nitric oxide ean contribute to damage in neurological diseases including multiple sclerosis Parkinson's disease = Stroke Alzheimer's disease The Microglia [= Microglia are mediators of the production of inflammatory cytokines and contribute to degenerative disease by increasing the risk of oxidative stress of neurons and apoptotic cell Seah, premature cell Etiology = Sty Mee ew foment * Along ist of conditions can increase neuronal oxidative stress and mediators of inflammatory conditions in the brain due to accumulated ‘damage over decadas,qulving: ~ acohel coneumsnon heavy metal oun exposure chron eueee ~ suboptimal B-vtamin nd anondart nun ~ ecsonta fay aoc ineicencies = exposure to ionizing rection = egarete eeking 4 areas ofthe etiology of Alzheimer's disease, in part, is urodegenerative disease "elated to inflammation of the rain through the release in ~'OxidatWe'sireaé: neurons of inflammatory mediators like interleukin-2, * Mitochondrial dysfunction interleukin-6, and tumor necrosis + Excitotoxicity factor alpha * Inflammation Lifestyle Factors Lifestyle Factors Fr * The initiation of an inflammatory response by allergens, toxins, or ‘emotions can clearly increase the oxidative stress burden ~upregulating the HPA axis and creating a more oxidant environment Habituation ‘Sin 2 Herr err 892127 ‘One of the most consistent findings in anxious depressed patients is elevated levels of cortisol Lifestyle Factors Se Seen hc oy Ass Nt ‘oes Glucocorticoids can lead to the premature apoptotic cell death of neurons we associate with increased risk of neurodegeneration or brain aging ‘tess Hormone Level and Suielce TWPRRHRTERSRLE Es nda Sac Lifestyle Expense (oF, ALM a 20 Nespeepamasny 2409708 * Constant environmental demand requiring sustained arousal invokes a biological transformation or brain signature that may be long lasting * With continued sustained arousal the hippocampus may undergo atrophy * Additionally, various endocrine and systemic disorders (eg elevated insulin, increased blood pressure) may also. manifest The Physiology of Adaptation ‘Sesh RL 203, uacensal Rao 2019) 17- 172 * Under circumstances in which stress impairs ‘hippocampal Long Term Potentiation, it facitates amygdaloid LTP * Under circumstances in which stress causes atrophy of denaitic processes in the hippocampus, the samo stressor causes ‘extension of processes by neurons in the ‘amygdala and in the bed nucleus of the stria terminalis, an amygdaloid projection site central to amity How? ‘eons pen no aan Mitochondrial DNA injuries can modify cognition and produce dysfunction at what is called the “intelligence level” pe Leading to Inflammation Pe 0.5 Pn cn *+ Because of decreased ATP production, the NMDA receptor becomes sensitized, ‘and when glutamate stimulates it, it allows €n influx of calcium into the neuron, which begins this progressive feed-forward cycle that utimately leads to progressive degeneration and, ultimately, cell desth * This links together excitotoxicity & mitochondrial disorders Literal Bumout ‘stan eon Soe wetseie te The NMDA pathway is an excitatory pathway for neuronal activity; when it is overstimulated, the result can be "neuronal burnout” eg. Oat name tl Aer nanan ‘ilocos anemetsdusah sand Pe Sans opie omc: vous aware ote Br Na ‘pienso There is a substantial overlap between AD and other neurodegenerative conditions Alzheimer's Disease eget nays cornomnenr ees oa pee ‘ron cose nay Asam) ahs arses * Alzheimer's disease (AD), accounts for about 70% of the dementia cases * Neuropathologically characterized by ‘dense and neuritic amyloid plaques and ‘cerebral intraneuronal neurofibrillary tangles ~ nelther plaques nor tangles correlate strongly Alzheimer's Disease Ss ee Dene Nie ae * Alzheimer’s disease presently afflicts some 4 milion people in the Ur States. The Census Bureau projects that by the year 2050, 79 million Americans will be 65 or older, and almost 18 million of them will be 85 or With the degree of dementia, loss of synapses older and at risk for Aizheimer's {nd nourone, and abnormalities of he elssese! cytoskeleton Alzheimer’s Disease Alzheimer's Disease Inonte Tat cand aeons eee aoe sein a * Alzheimer’s disease (AD) represents the third leading cause of death in the U.S. and the leading cause of dementia in the elderly population ‘+ In 1999, this disorder accounted for ‘approximately 170,000 deaths in the United States, placing it in third piace (7.1% of total deaths) Ipc fst da nema pi th es Sa Ne heed Seema * The yearly cost of AD in the United States is estimated to be $100 bilion * The cost of treating each patients estimated to be $195,000, with a significant amount ofthis cost being attributed to loss of productivity of the Patient and caregiver and to costs sustained by the family Alzheimer's Disease ‘Stree ke hl nets = From an anatomic point of view, AD is characterized by an atrophy of the cerebral cortex and by a massive loss of cortical neurons and cholinergic projections made by the nucleus basalis towards the cortex Alzheimer’s Disease Saeeesoumet sen emma ra canna ne From a histopathologic point of view, there is a diffuse presence of extracellular and perivascular neuritic plaques and intracellular neurofibrillary tangles in the cerebral parenchyma How? eat enn Denon ad been te aspen noes Morons rT ee. * In AD, the amyloid plaque is the focus of a microglial inflammatory response which increases cytokines, inducible NO synthase, complement, and acute phase proteins. Amyloid beta (AB) induces inflammatory responses in microglia il How? ‘Sonepat cons acne owt als PTS pempeneqpemnemeet erty tascy oe seat * Inflammatory mechanisms and more specifically activated microglia may contribute to the neurodegenerative process of Ads. not only as a purely secondary Phenomenon but also as a possible primary source of its clinical pathology When? Pen Ma 6. Toen ne pr nnd ‘Fetinad inert ono ks hse SSS + Annual neurological assessment of 62 initially nonsymptomatic individuals in the ppre-AD age bracket with post-mortem pathological changes in their brains of functional neurological signs and symptoms found a close association between the early-stage onset of these: ‘symptoms and the existence of neocortical plaques When? Ps Moe Tange an pei nama ag el ote ry arr The data suggest that the early loss of cognitive function may be @ predictor of the onset of Alzheimer’s Etiology, Genetics? Aeron enn fal Ah me Se See The apoE4 genotype is more ‘susceptible to brain inflammation Etiology, Genetics? ae ‘The apoE4 genotype is more susceptible Alzheimer's disease Etiology, Genetics? * HIV-infected subjects who have an apoE4 allele had excess dementia and peripheral neuropathy * Those with an apoE4 carriage had higher incidence of Alzheimer's disease Etiology, Genetics? S05 nano cmc Panta he Up May, 8. + ApoE4 genes, either single or double ‘@poEé alleles, mark and track against both cardiovascular disease risk and neurodegeneration —Hypethomocysteinemia? ‘sete fete osm thc ety ‘iow Davo oe Can Sarees a * Increases in vascular risk factors, serum homocysteine, apoE4 load, and neuroimaging pathology were found not ‘only in dementia but also in dysmentia and in patients with only subjective symptoms. ‘+ Homocysteine levels correlated inversely with cognitive performance. Etiology, Genetics? * "itis also important to emphasize that many people who carry the apoE allele do not develop Alzheimer's, so there must 'be other genetic andlor environmental factors involved. ... The hope for the future ‘must be that biochemical studies will reveal how apoE is involved in the processes that go awry. ...” aa The Context of Life ope R208 Aan i Med FAT, Gene environment interaction is Disease as Multifactorial {Cooper RS. 2008 Aan intern Med! 139457-40, ‘The genetic component of all complex described as Context dependency traits, such as hypertension, arthritis, ~ conditional nature of the and cognitive function, is influenced 2 whence by a broad range of effects spread Seen ee ce eres, ‘across many single nucleotide polymorphisms in many genes What do we expose our DNA to? Genetics DNA methylation-related processes are involved with atherosclerosis, diabetes, cancer, and neurodegeneration We are no longer peas in Mendel’s garden Therapy ‘Attempts to Heal Acetyicholinesterase Therapy? ‘Sez eof ae Met a mao iat ‘Semen orem ter aw ao ‘The consistent loss of cholinergic markers (choline acatyransierase, acetyicholinesterase, and pi ic Tuscarinic receptors) in the AD brain has prompted the development of acetyicholinesterase inhibitors with the aim of increasing acetylcholine levels in the brain Acetylcholinesterase Therapy? ‘Sorenson Nr sss This approach has been consistently shawn to produce symptomatic effects but has not had a significant impact on the natural history of the disorder Antiinflammatories, A Therapy? RGAe an wp stage ame anyway Nar ‘Soccer There is 2 reduced incidence of Alzheimer's disease in patients who take either NSAIDs or H2 receptor antagonists regularly Antiinflammatories, A Therapy? Sere Almost 20 retrospective studies have already shown the protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in populations with a long history of NSAID consumption which would reduce the AD prevalence by 50% and delay its onset by 5— Zvears Antiinfiammatories, A Therapy? ‘sre sont s asa me an ant Soop corer sonmnoepy esas 2 a Sean * Other studies with antiinflammatories (diclofenac, hydroxychioroquine) or nimesulide did not demonstrate a Positive effect on AD progression * This possibly indicates that influencing this neuroinfiammation should be done in an early stage and maybe for a prolonged period of time Antiinflammatories, A Therapy? ‘aM, Fans DL sre ae ecto ee oe ear nu Reet ar 8a 8, ‘There are compelling epidemiological data demonstrating that a subset of NSAIDs provide protection in AD, and long-term use is accompanied by ‘significant reduction in activated microglia Antiinflammatories, A Therapy? ela, Fete DL Epes an tne ce nie ‘See yan owes a 08440 8. + The precise mechanisms responsible for NSAID protective effects are not yet clear. * Because ibuprofen and indomethacin also bind to and activate PPAR, ithas been ‘suggested that the protective effects of NSAIDs may be mediated, in part, by activation of PPAR Antiinflammatories, A Therapy? ‘Snhaet moe Vassum te ONC * Antiinflammatorys activate peroxisome proliferator-activated receptors (PPARs), in Particular the PPARc isoform, whose ligands include thiazolidinediones and some NSAIDs. * The mechanisms subserving anti- inflammatory effects ot PPARc agonists are ‘not conclusively established effects on |jB could contribute to their therapeutic effects in disease Modes of Degeneration Mechanisms ‘SBosyemmestnooaos Rant har ea Spe Several studies have suggested that transcription factor NF-jB plays a role in the etiology of AD pathogenesis Mechanisms ‘ent MT Fei OL. Erect and cn ite i ‘eyes prt Nea hrs OAS, * Despite an increasing understanding of the roles that NF-jB activation plays in inflammatory responses and cell damage in neurologic disease and trauma, studies of its regulatory factors, namely the JB proteins, re limited Mechanisms otea hie DL. Epona cto nti oe ae pun Ror a 8 Ha * Microglial phagocytosis is inhibited by NO and increased by NOS inhibitors, suggestin that anti-inflammatories whi reduce NOS2 expression might enhance amyloid removal Mechanisms Herala MT, Fein OL fapnsn a fo te ‘Sees n oven. Near! hr 204 140 * In glial cells, increased levels of HSPs, including that ofthe Ba protein, provide ‘antiinflammatory effects, yet increased HSPs have been shown to increase amyloid phagocytosis * Thus, itis possible that PPARc agonists, rather than reducing, could enhance microglial phagocytosis as a consequence of reduced iNOS and increased HSP ‘expression 10 Mechanisms. ‘erat MT Fontan Lx sino nel he (canes now I ewaemonl har F305 ae Ie PPAR agonists may represent a class of agents able selectively to reduce NF-jB-dependent inflammatory expression without reducing their anti- Mechanisms ‘tent Fermin DL. Exxeneen ana incon of cin ae ‘Seton nous Jnl Mar SC a Rapid induction of {ja occurs in response to NF-jB activation, providing an autoregulatory loop to limit inflammatory gene expression * However, the BBB is a selective barrier inflammatory responses = Mechanisms A call for research of herbal eee remedy affects = SB is Leg bone connected — to the thigh bone Bi i ie A Causative Factor, Cytokines oe oie ae aaa * The construct of the BBB as an oe * absolute barrier has kept bodily enaeenceinmapaemense: pathophysiology mostly apart fhe cies manfestaione of dcoase from neurology Transcriptional, translational and other ‘molecular control mechanisms protect the host from excessive cytokine production 1 ‘A Causative Factor, Cytokines Sms vinwe has ts nome datnt * Autonomic dysfunction has been associated with human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis; whether this dysfunction results from the inflammatory ‘component of these diseases, or is ‘actually an underlying cause, is not clear The Liver, Site of Fire/Heat “my 0) Tie oe ao 4, + Recently, vagal connections tothe liver have been identified as involved in an “inlarnmatory reflex” are + The ver is tho largest ste of fixed macrophages ‘and the brain regulates inflammatory (stress) ‘oytokine production inthis pathway + The nervous system reflexvely regulates the inflammatory response in real time, just as it ‘controls heart rate and other vital functions ‘The ‘cholinergic ant-inflammatory pathway’ in canine 5 Atom me ‘oun nom ate * The inflammatory reflex - the autonomic nervous system detects the presence of inflammatory stimuli and modulates ‘cytokine production ~Afferent signals to the brain are transmitted via the vagus nerve, which activates a reflex response that culminates in efferent vagus nerve signaling (remember the gut (2:1) Catecholamines Increased catecholamines with increased oxidation can be associated with neurodegeneration “The ‘cholinergic ant-nflammatory pathway’ Ses heten eae momma * The ‘cholinergic anti-inflammatory pathway, efferent activity in the vagus nerve releases acetylcholine (ACh) in the vicinity of macrophages within the reticuloendothelial system ~ACh can interact with macrophage nicotinic ACh receptors, leading to cellular deactivation and inhibition of cytokine release The Second Brain 12 Beyond The Brain Spc andor sys maa aes tcc ah ‘Soe sry ws Se ‘A trigger for inflammation: antigenic insults + Headache and central nervous system white matter abnormalities (measured by MRI) were associated with gluten sensitivity ‘* When gluten was removed there was ‘symptomatic response and improvement in their MRIs rain Mf ofa patient with gluten ataxle showing rapid onset ‘of eerebela atrophy over a period of 15 months beore the lagnosis of gluten ataxia. Beyond The Brain "an ton un nny prin * There is @ very high statistical correlation between nonspecific gluten enteropathy and early-stage dementia * The authors propose a causal link between low-level gluten sensitivity and dementia Beyond The Brain eda Mra RA, Dnderones Gh Git say: {eyes her Bal Tosaarete Tt * Patients with neurological dysfunction of obscure etiology demonstrated a high prevalence of circulating antigliadin antibodies (@, IgA, or bot in 57 % vs. § % in neurological controls 812% in normal controls) + There is neatly a tenfold increase in tis neurological dysfunction or dementia in gluten- ‘sensitive individuals compared to those are not luton sensitive = Beyond The Brain aso Dec hn snip el ‘ner iaua!ogaraes * This link may be created through activation of the gut-associated lymphoid tissue (GALT) ~ increased release of proinflammatory markers from the GALT like IL-2 and TNF Beyond The Brain ‘Sei Ge hese Caen srr sce ch ‘im emir oes. This result points to connections ‘among the gut, the immune system, the gut-associated-lymphoid-tissue (GALT), and the blood/brain barrier transference of that information through inflammatory mediators. a 13 Beyond The Brain hE ae * 42% of pts with Crohn's disease and 46% of pts with ulcerative colitis have ‘small white-matter lesions on magnetic resonance imaging * These changes were found in only 16 percent of healthy controls Beyond The Brain SSDS NRA atemere + Thar is an inerrlaionsip between ateraton in mtochonealuncton sun resistance, and lowered energy production (mitochondrial uncoupling). + As much as 40% educton can be cbservedin mitochondlendatve and Dhosphenlation acy nnn resistance Beyond The Brain SSSA en Metabolic syndrome is associated with the risk of cognitive decline Beyond The Brain Monit mre Th eines a a a! ‘tro irnwenso ie eee * Alterations of the cysteine-to-sulphate ratio may also be an assessment/prognostic indicator of alteration and detoxification that tracks back to potential risk to Neurodegeneration * Low sulphate-to-creatine ratios are associated with poor detoxification Speculation ‘Although unproven, scientifically, common Sense dictates that the strategies always Used by phytotherapists may be Particularly useful in at least the delay of ‘onset of neurodegenaration = Improving the dit = Cooling the iver Enhancing digestion ~ Balancing the system = Enhancing “organ reserve” 14 Nutritional Affects Genes respond to the environment (informational input) Hippocrates “Let food be thy medicine and medicine be thy food”

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