Dementia overview


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Dementia overview

  1. 1. Types of dementia, Pathphysiology of Alzheimer’s disease, New diagnostic criteria and guidelines for Alzheimer’s disease, Current and future psychopharmacological interventions in Alzheimer’s disease.
  2. 2. Dementia – a growing epidemic In 2012 -5.4 million Americans have dementia of all causes. In 2050- it is estimated that 15 million Americans will live with dementia. Every 68 seconds someone in America develops dementia. It is estimated that nearly 500,000 new cases will be diagnosed this year alone. Worldwide 36 million people are believed to live with dementia. By 2050, if breakthroughs are not discovered, the rates could exceed 115 million.
  3. 3. DefinitionDementia consists of: memory impairment (amnesia), deficits in either language (aphasia), or motor function (apraxia), recognition (agnosia), or executive function, such as working memory and problem solving. personality changes can also be present (sometimes even before the memory impairment)
  4. 4. Not Every Memory Disturbance IsDementia Age-related memory-impairment (ARMI)  Self perceived memory loss  Over age 65 – prevalence around 40% = 16 million in US  About 1% of which eventually develop dementia Minor Cognitive Impairment (MCI)  More severe memory loss, little/no functional impairment  Around 10% over 65 – does not necessarily develop to AD Alzheimer’s Disease (AD)  Around 15% of those with MCI convert
  5. 5. Not All Dementias are Alzheimer’sDisease
  6. 6. Mixed Dementias It is possible to have more than one dementia, and in fact many patients have both Alzheimer’s disease and either dementia with Lewy bodies or vascular dementia.
  7. 7. Pathology of Alzheimer’s DementiaIn order for a dementia to be called Alzhheimer’s diseaseit has to present with both: AMYLOID PATHOLOGY - Beta amyloid plaques (extracellular) TAU PROTEIN PATHOLOGY - Neurofibrillary tangles (abnormal phosphorylation of tau proteins) (intracellular)
  8. 8. Amyloid Plaques
  9. 9. NORMAL PATHWAY: Processing of AmyloidPrecursor Protein into Soluble Peptides
  10. 10. ABNORMAL PATHWAY: Processing ofAmyloid Precursor Protein into A betaPeptides
  11. 11. Beta Secretase Inhibitors Merck: MK-8931 Lilly: LY450139
  12. 12. Gamma Secretase Inhibitors Merck: MK-8931 Eisai: E 2609 Lilly: LY2886721
  13. 13. Monoclonal Antibodies againstAbeta 42 *Solanezumab (Lilly) *Bepaneuzumaub (Pfizer)
  14. 14. AMYVID (Flobetapir)Visualizing Amyloid  Indicated for PET imaging of the brain to estimate the density of beta amyloid plaques in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive impairment.
  15. 15. Amyloid Cascade Hypothesis, Part One: increasedproduction of Abeta42
  16. 16. Amyloid Cascade Hypothesis, Part Two: A beta 42Oligomers Form and Interfere with SynapticFunction
  17. 17. Amyloid Cascade Hypothesis, Part Three: formation ofamyloid plaques causing inflammation
  18. 18. Amyloid Cascade Hypothesis, Part Four: amyloid plaqueinduces formation of tangles
  19. 19. The Role of Tau Protein
  20. 20. Tau Pathology
  21. 21. Amyloid cascade Hypothesis, Part Five: neuronaldysfunction and loss
  22. 22. DIAGNOSIS: 2011 Diagnostic Criteria for AD(emphasis on prevention)
  23. 23. Two kinds of AD: Familial andIncidental Autosomal dominant, early onset (5-10%) (mutations in the APP or gamma secretase) CHROMOSOME GENE 1 Presenilin 2 14 Presenilin 1 21 Amyloid PPIncidental is non-genetic it does not run infamilies.
  24. 24. Pre-symptomatic Entities1. Pre clinical AD ( recommendations are intended for research purposes).2. MCI (Minor Cognitive Impairment).
  25. 25. More Sensitive Screening
  26. 26. Core clinical criteriaNeuropsychiatric symptoms that: 1. Interfere with the ability to function 2. Represent a decline from the previous level of functioning 3. Are not explained by delirium 4. Cognitive impairment is detected by history taking and objective cognitive assessment 5. Impairment involves a minimum of two of the following domains:  Impaired ability to acquire and remember new information  Impaired reasoning and handling of complex tasks, poor judgment  Impaired visuospatial abilities  Impaired language functioning  Changes in personality or behavior
  27. 27. Diagnostic Overview1. Possible AD dementia2. Probable AD dementia3. Probable or possible AD dementia withevidence of the AD pathophysiological process.
  28. 28. Incorporation of Biomarkers intoAD Dementia CriteriaBiomarkers may be useful in three circumstances:1. Investigational studies2. Clinical trials3. And as optional clinical tools for use where available and when deemed appropriate by the clinician.
  29. 29. CSF: Decreased Aβ42 Amyloid Pathology PET : Amyloid imaging with AmyvidBiomarkers CSF: Increased total or phosphorylated tau PET: hypoperfusion Tau Pathology temporoparietal, precuneus MRI: Medial temporal lobe atrophy, Hippocampal atrophy,
  30. 30. William Utermohlen 1933-2007 Diagnosed with Alzheimer’s disease in 1995. 1967 (self portrait)
  31. 31. 1995
  32. 32. 1997
  33. 33. 1998
  34. 34. 1999
  35. 35. 2000
  36. 36. Cholinesterase inhibitors offermodest results The usual response to cholinesterase inhibitor therapy in Alzheimer’s disease is initial improvement that is statistically detectable on cognitive testing and perhaps noticeable to the caregiver but not necessarily to the patient. Such a response usually lasts about 6 months, at which point cognitive functioning as measured on cognitive testing is back to where it was before beginning the drug.
  37. 37. Donepezil (Aricept) Selective inhibitor of AChE, allowing more ACh to accumulate Once daily dosing Severe AD  Benefits for all outcomes at 6 months  Some indication of positive changes on ADL and severe impairment battery (SIB) scores More selective for brain than periphery  GI side-effects usually moderate and transient - nausea, vomiting, diarrhea No liver toxicity Hallucinations twice as common as placebo .
  38. 38. Rivastigmine (Exelon) Inhibits both AChE and the peripheral butylcholinesterase (BuChE) May be more selective for hippocampal AChE May be more useful for late stage AD, when gliosis increases BuChE Might interfere with plaque formation Increased incidence of GI side-effects, especially during dose optimization/increase
  39. 39. Galantamine (Razadyne, previouslyReminyl) Natural product isolated from daffodils and snowdrops Inhibits AChE; allosteric modulator of nicotinic receptors; synergistic at cholinergic synapses Nicotinic action may boost attention and behaviors caused by deficiencies of other neurotransmitters. Studies:  16 or 24mg/day, 24 wks, benefits in cognitive and global function  Moderate AD gained more advantage than mild AD BUT may be higher mortality than with the other AChEs
  40. 40. Memantine (“Artificial Magnesium”) Voltage-dependent NMDA antagonist that targets glutamatergic system Mild side effect profile  Dizziness, confusion, headache, constipation Dosing schedule:  Week 1 - 5 mg/day, Week 2 - 5 mg twice a day, Week 3 - 10 mg twice a day, Week 4 - 15 mg twice a day Administered with or without food No PK/PD interactions with donepezil or other renally- excreted drugs