Alzheimer disease


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Alzheimer disease

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  • The majority of Alzheimer’s Disease cases are sporadic1/1000 cases are hereditary (autosomal dominant AD) and have usually an early onsetThese are related to 3 genes: Amyloid Precusor Protein (APP) and Preseniline 1 & 2 genesRole of Apolipoprotein E 4 allele?
  • The accumulation of a fragment of the amyloid precursor protein or APP (the amyloid beta 42 residue fragment orAb-42) leads to the formation of plaques that kill neurons. Most cases of early onset AD are familial autosomal dominant disorders caused by mutations in APP, PS1, and PS2Various substitutions have been studied and they have found various mutations that cause the individuals to secrete a higher fraction of A-beta42 and/or A-beta43 peptides
  • APP has neurotrophic and neuroprotective properties. Mechanisms by which A and tau induce neuronal dysfunction and death may include direct impairment of synaptic transmission and plasticity, excitotoxicity, oxidative stress, and neuroinflammation
  • Amyloid precursor protein (APP) is the precursor to amyloid plaque. 1.APP sticks through the neuron membrane.2.Enzymes cut the APP into fragments of protein, including beta-amyloid.3.Beta-amyloid fragments come together in clumps to form plaques.
  • Abnormal phosphorylation of tau proteins makes them “sticky,” leading to the break up of microtubules. The resultingloss of axonal transport causes cell death. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. A protein called tau stabilizes the microtubules when phosphorylatedIn AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.
  • In late onset alzheimer’s, there are no specific gene mutations that are associated with the inheritance of the diseaseHowever, specific alleles of apoliprotein E4 (apoE) and alpha2 macroglobulin are associated with increased risk of alzheimers
  • Epsilon 4 allele of the Apolipoprotein E (ApoE) gene - confers risk Epsilon 2 allele of the Apolipoprotein E gene - confers protection Mechanism unclear; ApoE is a very low density lipoprotein that transports cholesterol Provides less efficient amyloid clearance Decreases neurite outgrowth in dorsal root ganglion neuronal culturesclusterin (CLU) - synapse turnoverPhosphatidylinositol-binding clathrin assembly protein (PICALM)- participates in clathrin-mediated endocytosiscomplement component (3b/4b) receptor 1 (CR1) genes may be involved in amyloid clearance through the complement pathway.
  • Every gene that is known to increase susceptibility to Alzheimer’s disease also modulates some aspect of calcium signaling
  • Inflammation in certain regions of the brain and strokes - risk factors for AD.
  • Long-term usage of anti-inflammatory drugs is associated with a reduced likelihood of developing AD. However trials investigating their use have failed to show positive results.Curcummin from the curry spice has shown some effectiveness in preventing brain damage in mouse models (anti-inflammatory properties?).Ginko? Inconsistent results.A 21-year study found that Coffee drinkers of 3–5 cups per day at midlife had a 65% reduction in risk of dementia in late-life.Galantamine is competitive,rivastigmine and donepezil are non competitive. All are reversible anticholinesteraseMemantine is a noncompetitive antagonist of the NMDA-type glutamate receptor. It interacts with the Mg2+ binding site of the channel to prevent excessive activation while sparing normal function – decrease excitotoxicity. Adverse effects of memantine include headache or dizziness, but are usually mild and reversible. The drug is excreted by the kidneys, and dosage should be reduced in patients with severe renal impairment
  • N-methyl-D-aspartate (NMDA) receptors. NMDA type results in excitotoxitcity in brain ( neurodegeneration and apoptosis)Atypical antipsychotics, such as risperidone, olanzapine, and quetiapine (Chapter 16), are the most efficacious therapy for agitation and psychosis in AD. Risperdone and olanzapine are effective, but their use is often limited by adverse effects, including parkinsonism, sedation, and falls (Schneider et al., 2006). In addition, the use of atypical antipsychotics in elderly patients with dementia-related psychosis has been associated with a higher risk of stroke and overall mortality (Douglas and Smeeth, 2008; Schneider et al., 2005), leading the FDA to order inclusion of a boxed warning in the prescribing information for all drugs in this class. Unfortunately, there are few effective alternatives.Mood stabilizers (Chapter 16) have been the focus of several trials for BPSD. Carbamazepine has shown some benefit in small trials but carries numerous risks in the elderly, especially the potential for drug-drug interactions. There is little evidence of benefit from valproic acid. Lithium is of considerable interest given its ability to inhibit glycogen synthasekinase, which is implicated in AD pathogenesis, but clinical trial results are limited and concerns persist about the narrow therapeutic window in elderly patients. Benzodiazepines (Chapter 17) can be used for occasional control of acute agitation, but are not recommended for long-term management because of their adverse effects on cognition and other risks in the elderly population. The typical antipsychotic haloperidol (Chapter 16) may be useful for aggression, but sedation and extrapyramidal symptoms limit its use to control of acute episodes.Antidepressants (Chapter 15) can be useful for BPSD, particularly when depression or anxiety contribute. Because of the adverse anticholinergic effects of tricyclic agents, serotonergic antidepressants are favored. These agents are generally well tolerated. Trazodone has modest benefits, but for the most part, selective serotonin reuptake inhibitors (SSRIs) are the preferred class of drugs. behavioral and psychiatric symptoms in dementia (BPSD) . Eliminating drugs likely to aggravate cognitive impairments, particularly anticholinergics, benzodiazepines, and other sedative/hypnotics, from the patient's regimen is another important aspect of AD pharmacotherapy.
  • Bypasses the gastrointestinal tract & not influenced by food intakeSmooth, continuous drug delivery (for continuous efficacy)Potentially reduced side effectsImproves treatment compliance
  • Neuropsychiatric Inventory (NPI)HallucinationsDelusionsAgitation/aggressionDysphoria/depressionAnxietyIrritabilityDisinhibitionEuphoriaApathyAberrant motor behaviorSleep and night-time behavior change (12 item version only)Appetite and eating change (12 item version only)
  • Ladostigil is a dual acetylcholine butyrylcholineesterase and brain selective MAO-A and -B inhibitor in vivo which was shown to antagonize scopolamine-induced impairment in spatial memory. It could also regulate APP processing, activate PKC and MAPK. Inhibition of neuronal death markers, prevention of the fall in mitochondrial membrane potential and upregulation of neurotrophic factors and antioxidative activity rationalize it as an anti-AD agent
  • Phenserineincreased cognition and regional cerebral metabolic rate for glucose in AD patients.Huperzine A, Chinese herb with reversibly and selectively acetylcholinesterase inhibition activityIt has shown its cognitive enhancement in AD at a dose of 0.4 mg and seems to be a potential treatment option for AD.
  • The cascade includes (a) NMDAR hyperactivation; (b) activation of the p38 mitogen-activated kinase (MAPK)–MEF2C (transcription factor) pathway (MEF2 is subsequently cleaved by caspases to form an endogenous dominant-interfering form that contributes to neuronal cell death)39; (c) toxic effects of free radicals such as nitric oxide (NO) and reactive oxygen species (ROS); and (d) activation of apoptosis-inducing enzymes including caspases and apoptosis-inducing factor. AIF, apoptosis-inducing factor; Cyt c, cytochrome c; nNOS: neuronal nitric oxide synthase
  • ADAS-cog is a regulatory-mandated measure for cognitive performance in clinical trials of Alzheimer drugs. On this primary outcome measure, separation from placebo was clear in both patch groups by Week 16. At the end of the study, all active treatment groups showed statistically significant superiority over the placebo group.1Exelon 9.5 mg/24 hours patch provided efficacy similar to the capsule.1 Exelon 17.4 mg/24 hours patch showed a treatment effect that was numerically superior to the capsule and the Exelon 9.5 mg/24 hours patch.
  • An anti-inflammatory strategy based on the observation that a cellular inflammatory response in the cerebral cortex is elicited by the progressive accumulation of A-betaBased on the observation that A-beta aggregation is, in part, dependent on the metal ions zinc and copper. This strategy reasons that chelation of these ions in vivo may prevent A-beta depositionDecrease homocysteine
  • Tramiprosate is a glycosaminoglycan (GAG) mimetic . Deprenyl, a neuroprotective agent used to slow ADprogress, was shown to increase α-secretase activity bypromoting ADAM10 and PKCα/ε translocationPpar- Evidence of reductions in Aβ levels, plaque deposition, and microglial-mediated inflammationThe addition of a nitric oxide moiety is believed to attenuate gastrointestinal bleeding and ulcer formation associated with NSAIDs. Alpha-tocopherol (vitamin E) and the monoamine oxidase inhibitor selegiline have antioxidant activity, which has been posited to protect neurons from the inflammatory effects of Aβ accumulation. Nerve growth factor stimulates growth of cholinergic neurons Leuprolide acetate is an antigonadotropin agent that is entering phase III testing in mild to moderate Alzheimer’s disease.96 The rationale for studying leuprolide is that age-related increases in luteinizing hormone may be a causal factor in Alzheimer’s diseaselithium and valproate inhibit Aβ production100 and that lithium reduces neurodegeneration and levels of tau protein in the CSF possibly by inhibiting glycogen synthasekinase 3.Beta secretase inhibitors – bafilomycin A Ly450139- semagacestatAab-001 – bapineuzumabEtazolateFDA PHASE: Phase II/IIa/IIbMECHANISMS: Stimulates the neurotrophicα-secretase (non-amyloidogenic) pathway and inhibits β-amyloid induced-neuronal death.
  • The following proteinases have the abilities of degradating Aβ peptide: neprilysin (NEP)Insulindegrading enzyme (IDE)PlasminEndothelin converting enzyme (ECE) 1 and 2 and angiotensin-converting enzyme (ACE).Studies have showed that APP intracellular domain (AICD) could upregulate NEP transcription and increase Aβ degradation . ImatinibA tyrosine kinase inhibitor, was shown to elevate AICD in H4 human neuroglioma cells, and this was accompanied by concomitant increases of NEP protein, mRNA levels, and activity
  • Statins have also been shown to have immunomodulatory effects, blocking the ability of a cytokine called interferon-gamma (IFN-gamma) to activate T- cells. Statins might therefore have a neuro-protective effect by lowering inflammation. Several studies have also indicated that therapy with statins may reduce lipoprotein oxidation and ameliorate free radical injury.
  • Clioquinol A phase II clinical trial with clioquinol, a metal-protein-attenuating compound that inhibits zinc and copper ions from binding to Aβ, led to improved cognitive function, decreased plasma Aβ42 level and zinc concentration as compared with control group.PBT2 was an orally bioavailable, second generation 8-OH quinoline derivative of clioquinol, and is advancing as a disease-modifying candidate drug for Alzheimer’s disease.
  • Bexarotene is a nuclear receptor modulator and ApoE activatorThe lipidatedApoE activates microglia and/or astrocyte to degrade Aβ. It decreased brain amyloid plaque burden and improved behavior functions in AD transgenic miceIn addition, the effect of ApoE on Aβ clearance is also ApoEisoform-dependent: with ApoE2 the strongest effect and ApoE4 was significantly less effective in promoting Aβ clearance.
  • Solanezumab –, Aβ clearance by binding to it
  • is a tryptophan metabolite, synthesized mainly by the pineal gland . Melatonin (N-acetyl-5-methoxytryptamine) Alter lipid levels of mitochondrial membranes induced by amyloid beta protein.
  • An anti-inflammatory strategy based on the observation that a cellular inflammatory response in the cerebral cortex is elicited by the progressive accumulation of A-betaBased on the observation that A-beta aggregation is, in part, dependent on the metal ions zinc and copper. This strategy reasons that chelation of these ions in vivo may prevent A-beta depositionDecrease homocysteine
  • Ginkgo bilobaEstrogen – Phase IIDocosa-hexaenoic acid (DHA)It is thought to work through an antioxidant mechanismReviewed randomized, double-blind, placebo-controlled studiesFour studies with 212 subjects in each placebo and drug groups using EGb 761 120–240 mg/dayResults: small but significant effect of 3–6 month treatment 120–240 mg of ginkobiloba extract on objective measures of cognitive functionSide effects: four reports of hemorrhageEstrogens are neuroprotective against oxidative stress, excitatory neurotoxicity, and ischemia in the brain.This may be attributed to its powerful antioxidant, antiapoptotic, neurotrophic as well as its antiamyloidogenic activities.Merlo et al. reported that estrogen can activate matrix metalloproteinases-2 and −9 to increase beta amyloid degradationomega-3(n-3) polyunsaturated fatty acid DHA is associated with a reduced risk for ADDHA maybe an effective treatment for AD by means of antiamyloid, antioxidant, and neuroprotective mechanisms
  • even dissolve the developed aggregates, which include
  • An anti-inflammatory strategy based on the observation that a cellular inflammatory response in the cerebral cortex is elicited by the progressive accumulation of A-betaBased on the observation that A-beta aggregation is, in part, dependent on the metal ions zinc and copper. This strategy reasons that chelation of these ions in vivo may prevent A-beta depositionDecrease homocysteine
  • Deprenyl can regulate APP processing through PKC and mitogen activated protein kinase (MAPK) signaling pathways may explain its clinical effect in the late stage of the disease. Another MAO-B inhibitor rasagiline is a bifunctional molecule which also has acetylcholinesterase inhibition activity.
  • Axona is a medical food that is metabolized into ketone bodies, which the brain can use for energy even when its ability to process glucose is impaired. Brain-imaging scans of older adults and those with Alzheimer's disease reveal a dramatically decreased uptake of glucose, the brain's preferred source of energy
  • The degeneration of the cholinergic neurons in the nucleus basalis of Meynert leads to a reduction in the cholinergic innervation in the cortical and subcortical regions. Lack of endogenous nerve growth factor (NGF) can lead to memory deficits, whereas rescues neurons from injury-induced cell damage and leads to associated memory improvements and thus NGF is good for gene therapy.
  • Alzheimer disease

    2. 2. OVERVIEW • What is Alzheimer Disease? • Causes of AD • History • AD and brain (Pathophysiology) • Hypothesis • Management
    3. 3. Although the risk of developing AD increases with age – in most people with AD, symptoms first appear after age 60 (5% incidence) AD is not a part of normal aging. Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and disorders cognitive function. What is AD?
    4. 4. HISTORY
    5. 5. History of Alzheimer’s Disease • In November 1906, at a German psychiatrists meeting, Alois Alzheimer presented the pathological findings on a brain of a 56 y.o. woman who died after a progressive dementia
    6. 6. The Case Auguste Deter • This 51 y.o. woman was admitted to Frankfort hospital in 1901 for progressive dementia. • She was under the care of Dr. Alzheimer until her death in 1906. He did an autopsy, examined her brain & described the typical abnormalities of what would be called later Alzheimer’s Disease.
    7. 7. History, Continued • This case did not prompt any reaction untill Kraepelin, in 1910, referred to it as “Alzheimer’s Disease” (presenile dementia) in the 8th edition of his psychiatry book
    8. 8. History Continued • 1962: Corselis: presenile & senile dementias have the same pathological abnormalities • 1983:Coyle et al: Acetylcholine deficit in the cortex • 1995: The first gene abnormalities in familial Alzheimer disease are identified (Presenilin 1 & 2)
    9. 9. CAUSES OF AD
    11. 11. Plaques and Tangles: The Hallmarks of AD The brains of people with AD have an abundance of two abnormal structures: An actual AD plaque An actual AD tangle • beta-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells • neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell Volicer L. Clin Geriatr Med. 2001;17:377-391.
    12. 12. HYPOTHESIS
    13. 13. b a g g APP Protein: (1) b-secretase cuts APP protein, giving: (2) g-secretase cuts this residue, giving: or Ab40 Fragment Soluble Ab42 Fragment Unsoluble, aggregates into plaques 1. BETA AMYLOID HYPOTHESIS
    14. 14. Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is though to be important for neuronal growth, survival, and repair. From:
    15. 15. Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or Ab. From:
    16. 16. Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell, forming the plaques seen in the AD brain. From:
    17. 17. Neurofibrillary Tangles Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles. 2. TAU HYPOTHESIS
    18. 18. • Presenilin 1 (PS1) and presenilin 2 (PS2) are highly homologous 43-50 kD proteins with eight transmembrane domains • Presenilin’s are crucial components of the enzymes that work to cleave APP at gamma secretase site (catalytic core), and mutations in presenilins cause the production of A-beta42 and A-beta43 peptides (insoluble forms of A-beta) Shen & Kelleher (2007), PNAS, 104:403-408. 3. PRESENILIN HYPOTHESIS
    19. 19. 4. APOLIPOPROTEIN E AND OTHER GENES HYPOTHESIS From Sleegers et al. (2010) Trends in Genetics, 26, 84-94, p. 87
    20. 20. • It has been hypothesized that brains of patients with AD may have lower levels of plasmin • The higher production of amyloid peptide together with less efficient degradation would to A-beta accumulation and aggregation 5. PLASMIN HYPOTHESIS
    21. 21. • Calcium modulates many neural processes, including synaptic plasticity and apoptosis • Increased intracellular calcium elicits the characteristic lesions of this disorder, including the accumulation of amyloid-beta, the hyperphosphorylation of TAU and neuronal death 6. CALCIUM HYPOTHESIS LaFerla, F.M. (2002) Calcium dyshomeostasis and intracellular signalling in alzheimer’s disease. Nature Reviews Neuroscience 3, 862-872
    22. 22. 7. FREE RADICAL HYPOTHESIS • Oxidative damage from free radical molecules can injure neurons. • A study shows that an elevated level of homocysteine is associated with increased risk of AD.
    23. 23. •Marked decrease in choline acetyltransferase and loss of cholinergic neurons in brain • Involves nucleus basalis in forebrain , frontal cortex and hippocampus •There is also noradrenergic and serotonergic depletion due to degeneration of brainstem nuclei such as the locus coeruleus and dorsal raphe. 8. NEUROTRANSMITTER HYPOTHESIS
    24. 24.'s%20Disease%20Pathway
    25. 25. MANAGEMENT
    26. 26. How is Alzheimer’s Disease managed at present? • Ideally, management should involve an interdisciplinary approach for assessment, treatment & education • The roles of nutritionists, caregivers, nurses, social workers and patients associations can be vital for the long term care • Pharmacological treatment – Cholinesterase inhibitors – Memantine
    27. 27. The 3 targets for Pharmacotherapy • Cognitive decline: memory, language, orientation, concentration, etc. • Behavioral abnormalities: delusions, aggressiveness, anxiety, depression, psychosis etc.. • Activities of Daily Living: dressing, bathing, feeding, use of household appliances, etc.
    29. 29. Galantamine
    30. 30. Rivastigmine patch: a new approach to dementia therapy
    31. 31. Smooth and continuous drug delivery over 24 hours Graphic representation (not „real‟ data) Increased side effects Poor activity “Optimal therapeutic window” Druglevelintheblood Peak Oral Dose Trough Patch Time
    32. 32. Other cholinesterase inhibitors
    33. 33. Dimebon (latrepirdine) -Phase III -Cholinesterase inhibitor and also a NMDA-antagonist
    34. 34. Ladostigil - Combined neuroprotective effects with monoamine oxidase (MAO) -A and -B and cholinesterase inhibitory activities in a single molecule, - Phase II clinical trial
    35. 35. Nicotine • Nicotine is a cholinergic agonist that acts both postsynaptically and pre-synaptically to release acetylcholine • Nicotine evoked improvement in learning and memory is mediated through neuropeptide Y
    36. 36.
    37. 37. MEMANTINE
    38. 38. Memantine
    39. 39. Winblad et al Int J Geriatr Psychiatry 2007
    42. 42. Vassar, R., and Bennet, B.D. (1998) Beta-secretase cleavage of alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 5440-5464
    43. 43. Aβ-degrading enzymes (neprilysin) Imatinib • A tyrosine kinase inhibitor, was shown to elevate NEP protein, mRNA levels, and activity in human neuroglioma cells Valproic acid • Up-regulating NEP expression and activity in human neuroblastoma SH- SY5Y cell lines. Estrogen Green tea Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
    44. 44. M1 muscarinic agonist • Activation of M1 mAChRs – Enhanced secretion of sAPPα, (via α-secretase activation), – Decreased Aβ (via γ-secretase inhibition), – Inhibits Aβ- and/or oxidative stress-induced cell death. Talsaclidine • Phase II • In a double-blind, placebo-controlled, and randomized clinical study in AD patients, treatment with talsaclidine decreased CSF Aβ about 20% as compared with the baseline
    45. 45. Statins • Phase II • Cholesterol-rich diet increased β-secretase processing of APP while cholesterol lowering resulted in decreased Aβ production
    46. 46. Metals
    47. 47. Clioquinol Phase II
    48. 48. Apolipoprotein E (ApoE) promotes Aβ clearance Bexarotene Phase II Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
    49. 49. Solanezumab Phase III
    50. 50. Melatonin - Phase III - This neurohormone prevents neuronal death caused by exposure to the amyloid beta protein. - It inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates. - Prevent the hyperphosphorylation of the tau protein in rats. Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
    52. 52. Prevention of phosphorylation of tau • Cyclin-dependent kinase-5 (CDK5) is a kinase suggested to phosphorylate tau in AD. • Glycogen synthase kinase (GSK)-3β has also been suggested as a drug target to inhibit tangle formation. Lithium and Propentofylline (PPF) • Phase II • It reduced the active form of GSK-3β and prevented the hyperphosphorylation of tau. Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
    53. 53. Davunetide • Neuroprotective • Phase 2 Dementia: update for practitioner. Columbia university
    54. 54. Prevention of the aggregation of tau • Methylene blue – phase II • Methylthioninium chloride • Phenothiazines, • Anthraquinones • Polyphenols • Thiacarbocyanine dyes • N-phenylamines, • Thiazolyl-hydrazides, rhodanines,
    55. 55. • TREATMENT BASED ON AMYLOID PATHOLOGY • TREATMENT BASED ON TAU PATHOLOGY • TREATMENT BASED ON OTHER MECHANISMS • Monoamine Oxidase Inhibitors • Resveratrol • DHA • Caprylidene • Cell transplantation and Gene therapy
    56. 56. Monoamine oxidase inhibitors Neurobiology of aging, 2000
    57. 57. Resveratrol • Phase III • Red wine bioactive compounds • Inhibition of Aβ aggregation, by scavenging oxidants and exerting antiinflammatory activities Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
    58. 58. Caprylidene • Medium chain triglyceride produced by processing coconut oil or palm oil • FDA Approved March 2009
    59. 59. DHA Phase III MECHANISMS: DHA is a major component of neuron membranes and has multiple functions, including modulation of presenilin.
    60. 60. Cell transplantation and gene therapy • Transplantation of cholinergic-rich tissue or peripheral cholinergic neurons ameliorates abnormal behavior and cognitive function • GENE THERAPY – NGF administration in a phase I trial – Aβ-degrading enzymes Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
    61. 61. Famous Alzheimer’s patients: Ronald Reagan, Charlton Heston, Rita Hayworth, George Fernandes