Alzheimer's Disease Past Paper PDF

ALZHEIMER DISEASE INTRODUCTION Alzheimer disease (AD) affects ∼7.5 million Americans of all ages and is a progressive illness of unknown cause characterized by loss of cognitive and physical functioning, commonly with behavior symptoms. PATHOPHYSIOLOGY  Genetic susceptibility to late on...

ALZHEIMER DISEASE INTRODUCTION Alzheimer disease (AD) affects ∼7.5 million Americans of all ages and is a progressive illness of unknown cause characterized by loss of cognitive and physical functioning, commonly with behavior symptoms. PATHOPHYSIOLOGY  Genetic susceptibility to late onset AD is primarily linked to the apolipoprotein E (APOE) genotype, but a genetic × environmental interaction may be at play. AD occurrence at a young age is seen in less than 1% of cases. These dominantly inherited forms are attributed to chromosomal alterations that affect processing of the amyloid precursor protein.  AD risk factors include age, decreased brain reserve capacity, head injury, Down syndrome, depression, mild cognitive impairment, and risk factors for vascular disease, including hypertension, elevated homocysteine, elevated low density lipoprotein cholesterol, low high density lipoprotein cholesterol, obesity, metabolic syndrome, and diabetes.  Signature lesions include intracellular neurofibrillary tangles (NFTs), extra cellular plagues in the cortex and medial temporal lobe, degeneration of neurons and synapses, and cortical atrophy. AD affected individuals appear to have a higher burden of plaques and NFTs in their younger years compared to age matched controls.  Proposed mechanisms for these changes include: (1) β amyloid protein aggregation, leading to formation of plaques; (2) hyperphosphorylation of tau protein, leading to NFTs; (3) synaptic failure and depletion of neurotrophin and neurotransmitters; (4) mitochondrial dysfunction; and (5) oxidative stress.  The amyloid cascade hypothesis involves a β­amyloid production and clearance imbalance, with aggregation and accumulation leading to AD. It is unknown if this is the primary pathology in most forms of AD.  Loss of cholinergic activity is the most prominent neurotransmitter deficit that correlates with AD severity. Cholinergic cell loss seems to be a consequence of AD pathology, not the cause.  Other neurotransmitters involved include: (1) serotonergic neurons of the raphe nuclei and noradrenergic cells of the locus ceruleus are lost; (2) monoamine oxidase type B activity is increased; (3) glutamate pathways of the cortex and limbic structures are abnormal; and (4) excitatory neurotransmitters, including glutamate, may be neurotoxic. CLINICAL PRESENTATION Early disease may be characterized by changes in learning and memory, planning organization, and mood. As the disease progresses, further declines in these domains, as well as changes in personality, judgment, speech, and spatial orientation are seen. In the late stages, functional decline may result in gait, swallowing, incontinence symptoms, and behavioral changes. Patients become increasingly unable to care for themselves. 22 Stages of Alzheimer Disease using Folstein Mini Mental State Examination (MMSE) Patient has difficulty remembering recent events. Ability to manage finances, prepare Mild food, and carry out other household activities declines. May get lost while driving. (MMSE Begins to withdraw from difficult tasks and to give up hobbies. May deny memory score 26–21) problems. Moderate Patient requires assistance with activities of daily living. Frequently disoriented (MMSE with regard to time (date, year, and season). Recent events recall is severely score 20– impaired. May forget some details of past life events and names of family and 10) friends. Functioning may fluctuate from day to day. Patient generally denies problems. May become suspicious or tearful. Loses ability to drive safely. Agitation, paranoia, and delusions are common. Severe Patient loses ability to speak, walk, and feed self. Incontinent of urine and feces. (MMSE Requires care 24 hours a day, 7 days a week. score 9– 0) DIAGNOSIS  AD is a spectrum beginning with an asymptomatic preclinical phase progressing to the symptomatic preclinical phase and then to the dementia phase. AD is a clinical diagnosis, based largely on identified symptoms and difficulty with activities of daily living revealed by patient and caregiver interviews.  Patients with suspected AD should have a history and physical examination with appropriate laboratory tests (ie, serum B12, folate, thyroid panel, blood cell counts, serum electrolytes, and liver function tests).  Structural imaging (ie, non-contrast enhanced CT or MRI) may be performed to identify structural abnormalities consistent with AD or other pathology, such as brain atrophy, vascular damage, or tumors. To exclude other diagnoses, cerebrospinal fluid analysis or an electroencephalogram can occasionally be justified. APOE genetic testing is currently not recommended.  Obtain information on medication and substance use; family medical history; and history of trauma, depression, or head injury. Rule out medications (eg, anticholinergics, sedatives, hypnotics, opioids, antipsychotics, and anticonvulsants) as contributors to dementia symptoms or contribute to delirium (eg, digoxin, nonsteroidal anti-inflammatory drugs [NSAIDs], histamine 2 [H2] receptor antagonists, amiodarone, antihypertensives, and corticosteroids).  The Folstein Mini Mental State Examination (MMSE) can help establish a history of deficits in two or more areas of cognition at baseline against which to evaluate change in severity over time. The average expected decline in an untreated patient is 2–4 points per year.  In the future, improved brain imaging and validated biomarkers of disease will enable sophisticated diagnosis with identified cognitive strengths and weaknesses and neuroanatomic localization of deficits. 23  TREATMENT Goals of Treatment: To maintain cognitive functioning and activities of daily living as long as possible, with a secondary goal to treat the psychiatric and behavioral symptoms. Non-pharmacologic Therapy  Identify the possible causative factors for cognitive and noncognitive symptoms, andadapt the caregiving environment to remedy the situation.  Sleep disturbances, wandering, urinary incontinence, agitation, and aggression should be managed with behavioral and environmental interventions whenever possible, for example, redirecting the patient’s attention and removing stressors and triggers.  On initial diagnosis, the patient and caregiver should be educated on the course of illness, available treatments, legal decisions, lifestyle changes that will become necessary, and other quality of life issues.  Primary prevention includes smoking cessation, increasing physical activity, andreducing midlife obesity, hypertension, and diabetes. Adherence to the Mediterranean Diet or Dietary Approaches to Stop Hypertension (DASH) Diet may reduce the risk of cognitive impairment or decline. Pharmacologic Therapy of Cognitive Symptoms  Consider the anti-amyloid monoclonal antibody (mAb) aducanumab for mild cognitive impairment (MCI). Titrate to recommended maintenance dose as tolerated.  In mild to moderate AD, consider a cholinesterase inhibitor (donepezil, rivastigmine, or galantamine) or aducanumab titrated to recommended maintenance dose as tolerated.  In moderate to severe AD, consider adding the anti-glutamatergic agent memantine titrated to recommended maintenance dose as tolerated; alternatively, consider memantine or cholinesterase inhibitor therapy alone.  A reasonable response may be a slowed decline in abilities and delayed long term care placement.  Simplify dosing regimens, taking patient and caregiver preferences into consideration medication adherence and persistence.  Treatment gaps may be associated with a loss of benefits when medication is stopped but this is controversial.  Behavioral symptoms may require additional pharmacologic approaches Cholinesterase Inhibitors  Table 2 summarizes cholinesterase inhibitor dosing. Donepezil, rivastigmine, and galantamine are indicated in mild to moderate AD; donepezil is also indicated for severe AD. No trials have assessed the effectiveness of one agent over another.  Successful treatment shows a MMSE score decline of less than 2 points per year with benefit lasting 3–24 months.  If rivastigmine or galantamine are interrupted for several days or longer, re-titrate starting at the lowest dose due to their short half-lives. Gradual dose titration over several months improves tolerability. When switching from one agent to another, a washout period is recommended.  Abrupt discontinuation can cause worsening of cognition and behavior in some patients.  Table below lists common medication adverse reactions and monitoring parameters. 24 Table 2: Adverse Medication Reaction Monitoring Reaction Adverse Medication Monitoring Comments Medication Parameters Discontinue at first sign Serious skin reactions ofskin rash, unless clearly (Stevens– Johnson not related Galantamine syndrome and acute Appearance of skin If signs/symptoms are generalized rash suggestive of a serious exanthematous reaction, consider pustulosis) alternative treatment and do not rechallenge Reaction spread Discontinue if evidence of beyondpatch size, disseminated allergic evidence of a more dermatitis appears Patients Rivastigmine Allergic dermatitis intense local reaction sensitized by patch (increasing exposure may not be able to erythema, edema, take rivastigmine by mouth; papules, vesicles), allergy testing and close and persistence of medical supervision symptomsfor more recommended than 48 hours after patch removal Dizziness, syncope, Dizziness is usually mild, Report of dizziness or bradycardia, atrial transient, and not related to falls, pulse, blood arrhythmias, sinoatrial and cardiovascular problems pressure, and postural atrioventricular block, blood pressure change Cholinesterase myocardial infarction Routine pulse checks at inhibitors baseline, monthly during Nausea, vomiting, titration, and every 6 Weight and GI diarrhea, anorexia, months thereafter complaints weight loss Take with food to reduce GI Signs or symptoms of Peptic ulcer disease, GI upset active or occult GI bleeding Usually transient, dose related bleeding GI adverse effects seen with initiation, dosage titration, or medication switch Frail patients or those with low body weight may experience more GI effects and significant weight loss, particularly when rivastigmine is prescribed or when titrating to donepezil 23 mg GI effects less prominent with transdermal versus oral rivastigmine Increased concern for patients at increased risk of developing ulcers (eg, history of ulcer disease or concurrently taking NSAIDs) Confusion may be observed during dose titration and is Headache, confusion, Report of dizziness or Memantine usually transient dizziness, hallucinations falls, hallucinations Constipation May mitigate GI effects GI complaints associated with cholinesterase inhibitors 25  MRI at baseline, prior to 7th and 12th infusions, or if symptoms suggest ARIA, to identify brain edema, Vigilance for ARIA and focal ARIA microhemorrhage, superficial Aducanumab neurologic changes siderosis Symptoms of recommended especially Hypersensitivit y headache, confusion, during dose titration and the reactions dizziness, visual disturbances, first eight doses and nausea Angioedema and urticaria (rare) ARIA, Amyloid related imaging abnormalities; GI, gastrointestinal; NSAIDs, nonsteroidal anti inflammatory drugs. N Methyl D Aspartate (NMDA) Receptor Antagonist  Memantine is used as monotherapy and in combination with a cholinesterase inhibitor and is indicated for moderate to severe AD, but not for mild AD. It is not metabolized but requires dosing adjustments in patients with renal impairment. It is usually well tolerated.  Combination therapy with cholinesterase inhibitors and memantine, individually or as Namzaric, is generally used for moderate to severe AD. It slows cognitive and functional decline compared to cholinesterase inhibitor monotherapy or no treatment. Memantine may help mitigate some of the GI effects seen with cholinesterase inhibitors. Anti amyloid Monoclonal Antibody  Four humanized, immunoglobulin G1 mAbs have been designated as AD breakthrough therapies by the FDA (ie, aducanumab, lecanemab, donanemab, and gantenerumab). Aducanumab was controversially approved for use in MCI due to AD and mild AD.  Dosing for aducanumab, outlined in Tables 53 2 and 53 3, discusses its adverse effect monitoring.  The potential degree and duration of clinical benefit of anti amyloid antibodies remlaarignesly unclear. Other Medications  Use of estrogen, NSAIDS, prednisone, statins, or Ginkgo biloba is not recommended to prevent or treat dementia. Do not use Ginkgo biloba in individuals taking anticoagulants or antiplatelet medications, and use cautiously in those taking NSAIDs.  Vitamin E is under investigation for AD prevention and is not recommended for treatment.  There is currently insufficient evidence to recommend omega 3 fatty acids or medical foods such as Axona, Souvenaid, and Cerefolin NAC for treatment of AD. Pharmacologic Therapy of Neuropsychiatric Symptoms  No medication is FDA approved for the treatment of AD behavioral and psychological symptoms of dementia (BPSD) that are: (1) psychotic; (2) hyperactive (eg, inappropriate or disruptive behavior); (3) affective (eg, depression); and (4) apathy.  General guidelines include: (1) reserve for situations where nonpharmacologic failed; (2) starting with reduced doses and titrating slowly; (3) monitoring closely; (4) periodically attempting to taper and discontinue medication; and (5) careful documentation.  Cholinesterase inhibitors and memantine may be beneficial in treating BPSD but they do not reduce acute agitation. Avoid anticholinergic medications as they may worsen cognition. 26  Antidepressants  Antidepressants may help manage anxiety, apathy, as well as agitation and aggression.  A selective serotonin reuptake inhibitor (SSRI) can be used to treat depression with the best evidence for sertraline and citalopram. Tricyclic antidepressants are usually avoided. Antipsychotics  Antipsychotic medications have traditionally been used for psychotic and but the risks and benefits must be carefully weighed.  Second generation antipsychotics (ie, aripiprazole, risperidone, olanzapine, and quetiapine) are more effective compared to placebo; however, the higher risk of adverse effects and mortality offset this benefit. They should be restricted to patients with severe symptoms not responding to other measures. Taper treatment as early as possible and rarely used beyond 12 weeks. ✔ Common adverse medication reactions include somnolence, extrapyramidal symptoms, abnormal gait, worsening cognition, cerebrovascular events, and increased risk of death (black box warning). Miscellaneous Therapies  Evidence for benzodiazepine use is lacking and is not advised due to significant AD reactions.  Use of antiseizure medications (also known as mood stabilizers), carbamazepine, lamotrigine, pregabalin, and gabapentin, may be alternatives for agitation, but evidence is conflicting.  Use of valproic acid is no longer recommended due to severe adverse effects. EVALUATION OF THERAPEUTIC OUTCOMES  At baseline interview both patient and caregiver to identify target symptoms; define therapeutic goals; and document cognitive status, physical status, functional performance, mood, thought processes, and behavior.  Use a validated scale to assess cognition, activities of daily living (eg, the Bristol Activities of Daily Living Scale), and behavioral disturbances (eg, Neuropsychiatric Inventory Questionnaire) to quantify symptom changes and functioning.  Observe carefully for medication efficacy, need for dosage adjustments, adherence, potential adverse medication reactions, and document the method and frequency of monitoring.  Medication changes and adjustments should occur at 2–4 and 8–12 weeks after initiation, with assessments being repeated every 3–6 months thereafter. Several months to 1 year of treatment may be required to determine whether medications for cognition are beneficial.  Medication deprescribing for people with AD is aided by the availability of depot therapy. When to stop treatment due to lack of efficacy, if ever, is controversial 27