Alzheimer’s disease full

A presentation about Alzheimer's disease, it's definition, it's etiology, its mechanism of development as well as actual treatment and developing treatments.

1. ALZHEIMER’S DISEASE Fotso Bennis Mounir Scientific supervisor: PhD, Associate Professor Zhadan S.A. Department of Pathological Physiology Belarusian State Medical University, Minsk

2. Defining and understanding Alzheimer Alzheimer's disease (AD) is a chronic neurodegenerative disease with a slow start and which gets worse with time, the most common form of dementia, a brain disorder that leads to progressive decline of its function. It is marked by amnesia and loss of cognitive abilities, severe enough to disturb the normal life of the person affected. As the patients’ condition declines, they tend to isolate themselves from family and society. Death is then caused by gradual loss of bodily functions . The deterioration of the brain is due to a build up of amyloid plaques within neuron and neurofibrillary tangles.

3. HISTOLOGY Amyloid Plaques The body produces normally some protein fragments called amyloid. The β- Amyloid comes from an amyloid precursor protein (APP) and is normally broken down and eliminated in healthy brains. However, in Alzheimer’s disease, the fragments accumulate to form hard plaques. Neurofibrillary Tangles They are insoluble twisted fibres, consisting of Tau proteins and forming part of the microtubule. The microtubule is involved in nutrients’ transport from one part of the nerve cell to another. In AD, the tau protein is abnormal and the microtubules collapse.

4. Etiology The cause and reasons of AD is still not know to this day. However, many theories have been formulated regarding the development of the disease. It is however important to mention that genetics are involved as well and there’s a higher risk of contracting Alzheimer if the diseases has occurred previously in the family. First is the cholinergic hypothesis: the oldest, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The second is the amyloid hypothesis: which postulates that extracellular amyloid beta A β deposits are the fundamental cause of the disease. Third , we have the Tau hypothesis: it proposes that tau protein abnormalities initiate the disease cascade. Finally , other hypotheses state that the poor functioning of blood-brain barrier may be involved

5. Epidemiology Age is the greatest risk factor 4 Affects 10% of population over the age of 65² Affects 35% in those over the age of 85² Women at greater risk because of longer life expectancy 5 Estimated 24 million have dementia, most have Alzheimer’s disease 4 United States of America among countries with largest number of affected individuals 4 Major Public concern due to medical costs 4 Two victims: patient and caregiver 4 Increase in elderly population 5 Baby boomers aging 5 Life span increase due to advancement in medical technology 5 Slow progression 4 on average live 7 years after diagnosis ( can span from 2 to 18 years) 4 Advanced stages require assisted living and nursing home care 4 ²Pinel, John P. J.(2011). Biopsychology, Boston, MA: Pearson education, Inc. 4 Ballard, Clive C., Gauthier, Serge S., Corbett, Anne A., Brayne , Carol C., Aarsland , Dag D., and Jones, Emma.(2011). Alzheimer’s disease, 377, 1019-1031. Retrieved from: http://search.proquest.com.libproxy.edmc.edu/docview/85824866?accountid=34899 5 Lichtenberg, Peter A., Murman , Daniel L., and Mellow, Alan M.(2003). Handbook of Dementia: Psychological, neurological, and Psychiatric Perspective: John Wiley & Sons. Retrieved from: http://www.web.ebsohot.com.libproxy.edmc.edu

6. Pathophysiology of the disease : genetics Reviews of twin and family studies have evaluated the genetic heritability of the diseases from 49% to 79%. Around 0,1% are of autosomal dominance, developing before the age of 65 and known as early onset familial AD. This form can be attributed to mutations in one of three genes: those encoding APP and presenilins 1and 2. Most cases, termed sporadic AD showed no autosomal-dominant inheritance and genetics act more as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E. Recent genome-wide association studies have found 19 other areas in genes affecting the risk. These are CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SIC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, CD2AP. A suggested mechanism of action is that when TREM2 is mutated, white blood cells in the brain are no longer able to control the amount of beta amyloid present . The mutation of this gene have shown 3 to 5 times higher risks of developing AD

7. Early onset Late onset Region 1q31-q42 p resinilin 2 IP5EN2I Region 19q13.2 a poliprotein E ( ApoE ) Region 21q1.4 amyloid precursor protein (APP) Region 14q23.4 p resinilin 1 IP5EN1I Region 10p13 AD7 Region 10q24 AD5 Region 12p11.23 q13,12 AD3 Region 12p13.3 p12,3 Alpha 2 macroglobulin Region 12q13.1 p13,3 Low density lipoprotein receptor-related protein 1

8. Pathophysiology of the disease : cholinergic hypothesis The oldest, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuro-inflammation. The hypothesis states that a possible cause of AD is the reduced synthesis of acetylcholine, a neurotransmitter involved in both memory and learning, two important components of AD. Thus it was proposed that degeneration of cholinergic neurons in the basal forebrain and the associated loss of cholinergic neurotransmission in the cerebral cortex and other areas contributed significantly to the deterioration in cognitive function seen in patients with Alzheimer’s disease. Further studies on the cholinergic system and AD demonstrated acetylcholine plays a role in learning and memory. When young adults perform memory and attention tasks, brain activation patterns are balanced between the frontal and occipital lobes, creating a balance between bottom-up and top-down processing. Normal cognitive aging may affect long term and working memory, though the cholinergic system and cortical areas maintain performance through functional compensation. Adults with AD presenting with dysfunction of the cholinergic system are not able to compensate for long-term and working memory deficits. Therefore, a disruption to the cholinergic system has been proposed as a consequence of AD rather than a direct cause.

9. Pathophysiology of the disease : amyloid hypothesis According this theory, the pathology of AD (Alzheimer’s disease) is due mainly to amyloid plaques formed by aggregates of Aβ peptide that result from the proteolytic cleavages of APP (Amyloid Precursor Protein). It is stated that AD develops according two mechanisms: mutations in APP or Presenilin 1 or 2 gene (which are the inherited forms of the disease) OR failure of Aβ clearance mechanisms by inheritance of ApoE4. This results in faulty Aβ degradation and increased Aβ42 production throughout the life, with gradual rise of A β 42 levels in the brain. Subtle disturbances in synaptic efficacy (neuron communication) occurs because of gradual deposition of as diffuse plaques. Microglia and astrocytic neurons are activated and initiate inflammatory response. Altered neuronal ionic homeostasis results in oxidative injury. Altered kinase/phosphatase activities lead to tangles formation. Soon, neuronal/synaptic dysfunction spreads and selective neuronal loss appears.

10. Pathophysiology of the disease : tau hypothesis This hypothesis states that Tau protein, a highly soluble microtubule-associated protein (MAP), is abnormally or excessively phosphorylated, resulting in the transformation of normal adult tau into PHF-tau (paired helical filament). Tau protein, through its isoforms, interacts with tubulin and stabilizes microtubule assembly. Mutations altering the function and isoform expression of tau lead to hyper-phosphorylation. Thus aggregation occurs. These hyper-phosphorylated tau disassemble microtubules and lock normal tau, MAP1, MAP2 and ubiquitin into tangles. This insoluble structure damages cytoplasmic functions and interferes with axonal transport, leading to cell death.

11. 25 Symptoms of Alzheimer’s Disease Alzheimer's disease cause the patients to experience problems with memory, judgment, thinking, making it hard for them to work or even doing the simples tasks in life. As the disease is chronic and slowly develops, many symptoms take time to occurred or better to say to be noticed. It is common that family members and friends had to look back to realize the moment the changes started.

12. SYMPTOMS CONT. Impaired memory and thinking – At early stages, this symptom manifests with the patient having difficulties remembering things and even learning new information. In late stages, it is a long-term well pronounced memory loss with the patient forgetting even the most personal informations about his life. Disorientation and confusion – It manifests with patient getting more and more lost without being able to realize that they are lost or even how they got to the place where they are. They even stop recognizing familiar places and situations. Later, they stop recognizing people and even lose every notion of time. Misplacing things – It starts with the patient forgetting where he put things he uses everyday such as glasses or keys. Later it gets even more pronounced and the patient ends up putting objects in places where they are not supposed to be placed. For example car keys inside bathroom. Abstract thinking – It begins with the patient having troubles with certain easy tasks, finding them harder than usual, for example, balancing a checkbook. In advanced stages, he may forget the use of numbers and even letters. Trouble performing familiar tasks – Normal daily tasks such as eating, getting dressed, walking and so on, become harder and harder to do until the incapacity to do them alone.

13. SYMPTOMS CONT. Changes in personality and behavior – It can manifests by access of anger, irritability or even restlessness and quietness. Sometimes, the patient can even develop paranoia, confusion or fear. Poor or decreased judgment – The patient tend to make irrational choices such as leaving the stove on fire, opening windows during winter, going out half-naked. Inability to follow directions – It gets harder and harder to follow and even understand simple instructions. It leads to the patient getting lost easily and wander around. Problems with language and communication – It is more and more difficult to recall and use names of simple objects such as chair, table, pen, book. Impaired visual and spatial skills – It becomes harder and ultimately impossible for the patient to differentiate shape and to rearrange items in a specific order or according to the shape.. Loss of motivation or initiative – Patients starts to show passiveness, empty stares, closure to the world Loss of normal sleep patterns

14. 28 Stage I: Mild Alzheimer's disease Signs and symptoms of mild AD can include: Memory loss and changes in expressive speech Confusion about the location of familiar places Taking longer to finish routine, daily tasks Difficulty with simple math problems and related issues like handling money, paying bills, or balancing a checkbook Poor judgment which leads to bad decisions Mood and personality changes Increased anxiety

15. 29 Stage II: Moderate Alzheimer's disease Signs and symptoms of moderate AD can include: Increased memory loss Shortened attention span Difficulty recognizing friends and family Problems with language, including speech, reading, comprehension, and writing Difficulty organizing thoughts Inability to learn new things or cope with unexpected situations Restlessness, agitation, anxiety, tearfulness, and wandering, especially in the late afternoon or evening (sometimes called sundowning ) Repetitive statements or movements Hallucinations, delusions, suspiciousness, or paranoia Loss of impulse control (for example, sloppy table manners, undressing at inappropriate times or inappropriate places, vulgar language)

16. 30 Stage III: Severe Alzheimer's disease Signs of severe Alzheimer's disease may include : Complete loss of language and memory Weight loss Seizures, skin infections, and difficulty swallowing Groaning, moaning, or grunting Increased sleeping Lack of bladder and bowel control Loss of physical coordination

17. 31 Pattern of symptoms over time in patients with Alzheimer’s disease

18. 32 Cognition   * Recall/learning * Word finding * Problem solving * Judgement * Calculation Function * Work * Money/shopping * Cooking * Housekeeping * Reading * Writing * Hobbies Behavior * Apathy * Withdrawal * Depression * Irritability IMPAIRMENT Adapted from Galasko, 1997 Clinical features of AD Mild stage of AD (MMSE 21­30)

19. 33 Cognition   * Recent memory (remote memory unaffected) * Language (names, paraphasias) * Insight * Orientation * Visuospatial ability Function * IADL loss * Misplacing objects * Getting lost * Difficulty dressing (sequence and selection) Behavior * Delusions * Depression * Wandering * Insomnia * Agitation * Social skills unaffected IMPAIRMENT Clinical features of AD Moderate stage of AD (MMSE 10­20) Adapted from Galasko, 1997

20. 34 Cognition   * Attention * Difficulty performing familiar activities (apraxis) * Language (phrases, mutism) Function * Basic ADLs ­Dressing ­Grooming ­Bathing ­Eating ­Continence ­Walking ­Motor slowing Behavior * Agitation ­ Verbal ­ Physical * Insomnia Clinical features of AD Severe stage of AD (MMSE <10) Adapted from Galasko, 1997 IMPAIRMENT

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22. 36 Alzheimer’s Disease: Impact on Patient Aggression Hallucinations Use the toilet Delusions Feed themselves Fear or panic Dress themselves Praxis Inappropriate behaviour Keep themselves clean Impaired perception Restlessness Answer the telephone Executive dysfunction Apathy Go out alone Language difficulties Anxiety Keep appointments Disorientation in time and place Confusion Drive Attention deficits Depression Memory loss Behavioural and psychotic symptoms Activities of daily living; unable to: Cognitive impairments Maintain their own finances

23. 37 Impact of Alzheimer’s Disease on the Caregiver

24. Methods of treatment Treatment of mild-moderate AD Choline esterase inhibitors (Improves cognition & daily activities. Effective for 6 months, early initiation of therapy, decreases troublesome behaviors) - Donepezil 5 mg/day 4-6 weeks, then 10 mg/day until max tolerated dose - Rivastigmine 1,5 mg twice a day then step up monthly to maximum 6 mg twice a day - Galantamine 8 mg/day monthly increase to 16mg/day maximum 24 mg/day Treatment of severe AD NMDA antagonists (Slows intracellular Ca accumulation and delay nerve damage) - Memantine ( Used in combination with Donepazil ) 5mg daily in a week then 5 mg twice a day up to 15 mg/day

25. Treatment of secondary symptoms Behavioral intervention Neuroleptic agents such as haloperidol, chlorpromazine. They are recommended in low doses in frail and elderly. Antidepressants & mood stabilizers like citalopram (20 mg/day max 40mg), sertraline & fluvoxetine (no benefits according Wintraub & Petrecca study), mirtazapine (no benefits according Banerjee study) Anticonvulsants like gabapentin and sodium valproate Anti inflammatory agents NSAID are thought to delay onset of AD even though a double blind placebo trial (Grundman et al 2003) showed that rofecoxib and naproxen have no effect on AD progression

26. EXPERIMENTAL THERAPY Anti amyloid therapy – Vaccination with amyloid species, monoclonal antibodies, IVIG containing amyloid binding antibodies, selective amyloid lowering agents, beta secretase inhibitors ( Tarenflurbil and Semagacestat ). Unfortunately, no phase 3 trials for this therapy have shown acceptable efficacy. Antibiotics for AD - Antibiotics of the class cholinesterase inhibitors may improve the condition of patients with AD. Daily doxycycline 200mg plus rifampin 300mg or placebo for 3 months. Reversal of excess Tau phosphorylation – Free radical scavengers (High dose of Vitamin E – 2000U/day – slowed the progression of AD for 2 years according the large double blind placebo trial by Sano et al 1997). However, because of the risks of cardiovascular complications, these are not recommended nowadays. Estrogen replacement therapy – – It was thought estrogen could improve cognitive abilities. Control Trials (RCT) with 351 points for 2 weeks showed no beneficial effects Cholesterol lowering agents – Some epidemiological studies linked cholesterol homeostasis and AD. RCT double blinded with 748 pts for 6 months showed no efficacy.

27. EXPERIMENTAL THERAPY cont . Selegelline – Acts as a mood stabilizer and improves cognitive functions. RCT trial conducted in 2010 without positive results. Tramiprosate ( Alzhemed ) – Homotaurine that binds to soluble and insoluble Amyloid Beta, protecting against amyloid neurotoxicity and reducing tau protein abnormal phosphorylation. RCT double blinded placebo controlled trial ongoing 2009. Cerebrolysin – Peptidergic drug coming from purified pig brain, thought to be neurotrophic and neuroprotective. RCT double blinded placebo controlled trial ongoing 2010 Latreperidine ( Dimebom ) – Anti-histamine, inhibiting burylcholine esterase, AchE , NMDA signaling pathway. RCT phase 3 trial ongoing Jan 2011 Nimodipine – Prevents Ca accumulation in neurons, causes vasodilation. RCT with 500pts conducted in March 2010 showed improved cognition and global impression with doses 90 mg/day & 180 mg/day for 12, 24, 52 weeks.

28. EXPERIMENTAL THERAPY cont . Metal protein attenuating compound(MPAC ) ( clinoquinol ) – Solubilizes and clears Amyloid Beta. RCT double blinded with 36 pts revealed no efficacy after 36 weeks of trial. Mertrifonate – Irreversible AchE inhibitor. RCT double blinded phase 3 study for 26 weeks showed improvement at a dose of 60-80 mg/day. Lecithin – Major source of choline. RCT double blinded placebo failed to show efficacy. Huperzine A – Reversible AchE inhibitor. RCT double blinded Chinese study with 482 pts revealed improvement, Transcutaneous electrical nerve stimulation (TENS ) – Changes neurotransmitters, helps in neuron regeneration. 3 RCT in Netherlands and Japan. Limited data, small improvement.

29. Current available therapy Characteristic DONEPAZIL RIVASTIGMINE GALANTAMINE MEMANTINE Chemical class Piperidine Carbamate Phenanthrenealkaloid Similar to Amantadine Primary m echanism AchE inh AchE inh AchE inh NMDA antagonist Other mechanism None None Nicotine modulator HT3 receptor antagonist Half life 70 h 90 min 7 h 70 h Metabolism Hepatic Renal Hepatic Hepatic

30. Combined clinical trial data for the three licensed acetylcholinesterase inhibitors: rivastigmine (♦), donepezil (▴) and galantamine (•) versus placebo (▪). BULLOCK R BJP 2002;180:135-139 ©2002 by The Royal College of Psychiatrists

31. sources http:// www.alz.org/alzheimers_disease_what_is_alzheimers.asp https:// en.wikipedia.org/wiki/Alzheimer%27s_disease https://halfhillfarm.com/2015/10/25/brains-of-alzheimers-disease-patients-show-signs-of-fungal-infection / https://www.alzinfo.org/articles/what-happens-to-the-brain-in-alzheimers-disease / https:// www.thinglink.com/scene/629317049302122496 http://memorylanecottage.com/about-alzheimers-and-dementia/how-the-brain-changes-during-alzheimers-disease / Alzheimer’s Association: http://alz.org/alzheimers_disease_4719.asp Brain Tour About.com Healths Disease and Condition, Carrie Hill, PhD MSN Health, Healthwise , http:// health.msn.com/health- topics/aging/ articlepage.aspx?cp-documentid =100097440 http:// www.mayoclinic.com/health/alzheimersdisease/DS00161 Pinel , John P. J.(2011). Biopsychology, Boston, MA: Pearson education, Inc. Ballard , Clive C., Gauthier, Serge S., Corbett, Anne A., Brayne , Carol C., Aarsland , Dag D., and Jones, Emma.(2011). Alzheimer’s disease, 377, 1019-1031. Retrieved from: http://search.proquest.com.libproxy.edmc.edu/docview/85824866?accountid=34899 Lichtenberg , Peter A., Murman , Daniel L., and Mellow, Alan M.(2003). Handbook of Dementia: Psychological, neurological, and Psychiatric Perspective: John Wiley & Sons. Retrieved from: http://www.web.ebsohot.com.libproxy.edmc.edu Alzheimer's disease beyond APOE by Michael A van Es 1 & Leonard H van den Berg 1 - Michael A. van Es and Leonard H. van den Berg are at the Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands . http://dementiatoday.com/the-genetics-of-alzheimers-disease-whats-new/

32. Sources cont. Harrisons internal medicine – 18 th edition www.clinicaltrials.gov www.thecochranelibrary.com www.alzheimers.org www.alz.org www.nia.nih.gov