Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Alzheimer`s Disease
Document related concepts
Transcript
Alzheimer's Disease By: Niazy B Hussam PhD Clinical pharmcy Alzheimer's disease A disease of the nervous system characterized by a progressive dementia that leads to profound impairment in cognition and behavior It is the most common form of dementia, affecting 5% of individuals over age 65 The onset of the dementia typically occurs in middle to late life, and the prevalence of the illness increases with advancing age to include 25–35% of individuals over age 85. Clinical Features Earliest Feature Memory loss Late Features Memory of remote events and overlearned informations (for example, date and place of birth) declines together with other cognitive abilities Orientation to time is impaired Declines in orientation to personal information and immediate environment Language deficits which gradually progress to a loss of all language skills Declines in abstract reasoning, judgment, and problem solving In the later stages of the disease, the individual is bedridden and requires full-time assistance with basic living skills Neuropathological Features Senile plaques Neurofibrillary tangles (NFT) Neuronal cell loss Other microscopic features include neuropil threads, Hirano bodies, granulovascular degeneration, and inflammation around plaque formations The areas commonly affected include the association cortical and limbic regions Senile plaques are extracellular and contain a core of an amyloid beta peptide (Aβ) that is derived from the cleavage of a much larger beta amyloid precursor protein (APP) Neurofibrillary tangle is a hyperphosphorylated tau protein producing a highly insoluble cytoskeletal structure that is associated with cell death Alzheimer's disease has been associated with dysfunction of several neurotransmitter systems Disruption of information transfer between neurons can occur with loss of presynaptic elements and reduction of the recognition sites at which the neurotransmitter acts Loss of or abnormalities in the receptor-operated ion channels and second messenger systems within cells may be related to neuronal dysfunction Deficits in cholinergic, serotonergic, noradrenergic, and peptidergic neurotransmitters have been demonstrated Diagnosis A definite diagnosis of Alzheimer's disease is made only by direct examination of brain tissue obtained at autopsy or by biopsy to determine the presence of senile plaques and neurofibrillary tangles. A clinical evaluation, however, can provide a correct diagnosis in more than 80% of cases Clinical evaluation: Clinical history Neurological and psychiatric examinations Laboratory tests are used to screen for medical conditions, including diabetes, renal dysfunction, hypothyroidism, infection, and vitamin deficiencies. Neuroimaging studies Risk Factors Advancing age Family history APOE 4 genotype Obesity Insulin resistance Vascular factors Dyslipidemia Hypertension Inflammatory markers Down syndrome Traumatic brain injury Pathophysiology of AD The pathophysiology of AD is largely unknown The Amyloid Cascade Hypothesis is the main proposed mechanism to explain the disease process Abnormal production or insufficient clearance of the Aβ protein is thought to result in extracellular amyloid plaque deposition, which in turn leads to secondary events, such as hyperphosphorylation of the protein tau and generation of NFTs, inflammation, excitotoxicity, and, eventually, cell death through activation of the apoptotic pathway APP α-Secretase β-Secretase sAPPα sAPPβ γ-Secretase γ-Secretase p3 NFTs Aβ Inflammation Oxidative Stress Excitotoxicity Figure 1 Amyloid cascade hypothesis in AD An alternate hypothesis considers NFTs at the center of the pathophysiological process NFTs are produced by hyperphosphorylation of the protein tau, which is usually responsible of stabilizing the axonal cytoskeleton. They lead to disruption in axonal transport and eventually to cell death In recent years, increased emphasis has been put on the vascular contribution to AD’s pathophysiology Treatment Cholinesterase Inhibitors: ChEIs improve symptoms of AD, but they do not alter its natural clinical course. Donepezil Rivastigmine Galantamine Glutamate receptor antagonist Memantin Management of Side Effects. ChEIs are associated with cholinergic side effects S/E are observed with all available ChEIs Dose-dependent Starting these agents at the lowest dose, and slowly titrating by no less than 4-week intervals to the minimally effective dose, helps to minimize these side effects The transdermal formulation of rivastigmine is associated with considerably less gastrointestinal cholinergic side effects Switching Agents ChEIs belong to the same general class, yet, their individual pharmacological properties make switching a feasible option for intolerance or for lack of clinical response In the case of intolerance, wait for complete resolution of side effects of the initial agent before switching to the second agent In the case of lack of clinical response, switching to the second agent can be done overnight, with quicker titration Discontinuation of Therapy Indications for discontinuation of therapy in AD 1. The patient and (or) their proxy decision maker decide to stop 2. Refusal to take the medication 3. Non adherence to the medication 4. No response to therapy after a reasonable trial 5. Intolerable side effects 6. Comorbidities making continued use of the agent risky or futile 7. Progression to a stage of the disease where there is no significant benefit from continued therapy Emerging Treatments Amyloid-Based Therapies Reducing Aβ Production Preventing Aβ Accumulation and Promoting Clearance Nonamyloid Strategies Tau-Targeted Therapies Other Downstream Processes to Target : Inflammation Oxidative stress Excitotoxicity Mitochondrial dysfunction
