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.
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.
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)
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
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.
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)
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.
Amyloid Cascade Hypothesis, Part One: increasedproduction of Abeta42
Amyloid Cascade Hypothesis, Part Two: A beta 42Oligomers Form and Interfere with SynapticFunction
Amyloid cascade Hypothesis, Part Five: neuronaldysfunction and loss
DIAGNOSIS: 2011 Diagnostic Criteria for AD(emphasis on prevention)
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.
Pre-symptomatic Entities1. Pre clinical AD ( recommendations are intended for research purposes).2. MCI (Minor Cognitive Impairment).
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
Diagnostic Overview1. Possible AD dementia2. Probable AD dementia3. Probable or possible AD dementia withevidence of the AD pathophysiological process.
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.
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,
William Utermohlen 1933-2007 Diagnosed with Alzheimer’s disease in 1995. 1967 (self portrait)
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.
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 .
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
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
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