Alzheimer s Bouwmeester 1 Understand the role of genetics plaques tangles and inflammation in the pathophysiology of AD a RFs 60yo genetics female ethnicity AA Hispanic i APOE 4 chromosome 19 late onset Alzheimer s 60yo 1 Typically respond better to medication therapy ii Presenilin 1 chr 14 Presenilin 2 chr 1 early onset 45yo iii Amyloid precursor protein chr 21 Down s Syndrome has 3 copies of this chromosome b Possible RFs CV risk factors that reduce blood flow to the brain and result in neuronal death i Heavy smoking dyslipidemia HTN DM obesity ii Head injuries trauma c Amyloid Plaque formation of beta amyloid plaques outside of the neurons i APP amyloid precursor protein is cleaved by alpha secretase at a different site in AD and creates a longer fragment called a beta amyloid these then congregate to form plaques around neuronal tissue ii The plaques cause oxidative inflammatory injury and ultimately synaptic failure d Neurofibrillary Tangles hyperphosphorylated insoluble tau proteins which form paired helical molecules in the axons that result in microtubular collapse within the neurons i Amount of tangles is correlated to severity of the disease ii Leads to synaptic failure cell injury and eventually neuronal death e Inflammatory Immunologic Hypothesis inflammatory response to amyloid protein resulting in a release of cytokines NO and other free radicals f Brain Effects cortex shrivels up thinking planning remembering hippocampus shrinks memories while ventricles grow larger g DSM V Neurocognitive Disorders NCD i Mild modest decline in one or more cognitive domains does NOT interfere with independent living ii Major significant decline in one or more cognitive domains impairment that interferes with independent living specify if with or without behavioral disturbance iii More than just cognitive features also looks at behavioral function decline h Dementia is an umbrella term to describe NCDs 4 different types memory language visual spatial disturbances delusions agitation abrupt onset stepwise deterioration executive dysfunction gait changes associated with Parkinson s visual hallucinations delusions fluctuating mental i Alzheimer s ii Vascular iii Lewy bodies status EPS risk be wary of FGAs dysfunction excessive eating drinking iv Frontotemporal personality changes making inappropriate jokes suggestions executive 2 Describe the diagnosis of AD in terms of labs imaging studies dementia differential screening versus staging tools and v Many have Mixed Dementia e g Alzheimers and vascular the interpretation and limitations of the MMSE a Imaging CT Scan MRI for structural testing amyloid PET Scan for functional testing i Indicated for 60yo focal neurological signs abrupt onset or rapid decline predisposing conditions atypical presentation ii Not done on everyone because they are pricey for example a 70yo man comes to clinic with s sx of Alzheimer s we are going to assume he has Alzheimer s and draw his labs below b Lab Tests TSH B12 folate B9 serum calcium liver kidney function electrolytes i Also targeted biomarkers for research screen for HIV if RFs are present c Delirium Screening CAM Confusion Assessment Method d Cognitive Screening Montreal Cognitive Assessment MoCA Mini Cog 10 is severe e Cognitive Staging Brief Interview for Mental Status BIMS Mini Mental State Exam MMSE i MMSE Scores 21 26 Mild 11 20 Moderate 10 Severe 3 Goals of Therapy a Maintain QOL b Maximize function c Enhance cognition d Treat mood behavior problems i Behavioral s sx quantify them based on severity and frequency ii Rule out other causes drugs acute medical conditions environmental factors e Ease caregiver burden i Difficult caregiving for those with dementia ii Caregivers at risk for depression and physical illness and may affect ability to provide adequate care iii Support for caregivers can help avoid premature institutionalization of the patient iv Most Alzheimer s caregivers have their own children to care of on top of their duties 4 Medications Be familiar with all ChEIs names dosage forms but only need to know dosing for donepezil and memantine a MEDS will not CURE AD it may slow the progression decline associated with AD b Cholinesterase Inhibitors ChEIs i Acetylcholine is reduced in patients with Alzheimer s Disease ii Cholinergic neuronal pathways are involved in many cognitive processes including memory attention learning iii Donepezil for mild severe s sx Initial dose of 5mg po qHS increase to target dose of 10mg po qHS after 4 6wks 1 2 High dose of 23mg only to be used if stable at 10mg for 3mo 3 Available in ODT 4 CYUP 2D6 and 3A4 metabolism iv Galantamine for mild mod s sx 1 Give WF po oral solution and transdermal formulations v Rivastigmine for mild mod s sx 1 Give WF po formulation in IR and ER vi AEs NVD limiting side effects CNS insomnia nightmares agitation anxiety panic muscle cramps weakness bradycardia tremor dizziness vii Caution with anticholinergic med use because counteracts this class of drugs can result in delirum and cognitive impairment viii Caution of excessive bradycardia if on BBs CCBs digoxin ix x If pt cannot tolerate one ChEI can start a trial on another ChEI If 3 6mo without efficacy may try to change from donepezil to galantamine no recommendations c Memantine for mod severe s sx i MOA blocks glutamate from overstimulation and cell death ii Available in po caps and oral solution iii Weekly titration to target doses 1 ER 7mg daily 14mg daily 21mg daily 28mg daily a Max 14mg daily in CrCl 30 2 IR 5mg daily 5mg BID 5mg qAM with 10mg qHS 10mg BID a Max 5mg BID in CrCl 30 iv AEs constipation HTN dizziness HA confusion coughing anxiety v Caution in using NMDA antagonists dextromethorphan and amantadine Severe s sx memantine monotherapy OR memantine ChEI combotherapy d e Therapy may be stopped after 6 9mo if no more efficacy is seen etc no recommendations available 5 Design a strategy for behavioral symptoms including non pharmacologic approaches and specific medications for each symptom consideration SE efficacy black box warnings a Agitation aggression depression anxiety apathy psychosis most patients with AD experience ALL s sx b 1st line Non Pharm Therapy i Cognitive Interventions ii Environmental Modifications iii Changes in Activity Demand iv Interpersonal Approaches reorientation reminders cues adjust noise level reduce clutter figure 8 walking reduce amount complexity of activities simplified language focus on patient s wishes concerns c 2nd line ChEIs