Alzheimer s Disease: Presentation & Prognosis

Transcription

1 Memory Alzheimer s Disease: Presentation & Prognosis James B. Pinkston, Ph.D. Clinical Neuropsychologist March 23, 2012 What is memory?... Why is memory important?... Learning Continuity Personality Functioning (home, work, etc.) 1 2 Memory Memory Acquisition, retention, & recall of material Encoding (acquisition) Learning the information / getting it in Storage (retention) Retaining and maintaining the information Retrieval (recall) Extracting and recalling the information Declarative memory Experiences, facts, or events Episodic context specific, often autobiographical Semantic context free, general knowledge Non-declarative memory Skills that are not verbalized or consciously inspected (e.g., motor learning) 3 4 Normal Aging Many cognitive functions decline with age Starting at about 20 YO! Some are more vulnerable than others Declining functions do so at different rates and uneven trajectories Normal Aging Evidence that memory declines with age Recent memory more than immediate and long-term memory Memory for names, isolated facts, lists Slower learning Slower / imperfect acquisition of new material Mental processing speed declines also Many memory problems likely reflect slowed rate of retrieval of specific information 5 6 1

2 Normal Aging Normal aging However: Elders compensate for minor changes in cognition Can maintain normal daily function Decline impairment Memory Dysfunction Memory loss alone dementia Many individuals with amnesia retain sufficient cognitive function not to be classified as demented However, nearly all persons with dementia have memory loss sufficient to be classified as amnestic Evidence that memory impairment is not necessarily part of normal aging process 7 8 Mild Cognitive Impairment Mild cognitive impairment (MCI) refers to individuals with mild memory impairment without other symptoms of dementia At high risk for developing dementia In addition to neuropsychological testing, MCI patients should be screened for treatable causes of memory impairment including depression, hypothyroidism, and vitamin deficiencies, etc. Mild Cognitive Impairment MCI is different from both Alzheimer s and normal age-related memory change People with MCI have ongoing memory problems but do not usually have other difficulties like confusion, attention problems, or difficulty with language 9 10 Mild Cognitive Impairment This memory loss is not great enough to make it significantly difficult for people to carry out everyday activities For example, some people with MCI may be forgetful, but they are still able to live on their own, unlike people with dementia Dementia Development of multiple cognitive deficits manifested by both: Memory impairment & Aphasia, apraxia, agnosia, or executive dysfunction Causes significant functional impairment Not a Delirium / impaired consciousness

3 Dementia Demented patients less aware of the extent of their cognitive deficits, particularly in the later stages May report improvement in their functioning with disease progression and declining self-awareness Dementia Progressive Dementias 85 90% Alzheimer s Disease 50 70% Other 15 17% Vascular Huntington s, Parkinson s Pick s / Fronto-temporal TBI, Anoxia, MS HIV, CJD, ALS Etc Dementia Prevalence of dementia with aging Increase more pronounced for women 13% among 77 to 84 25% among 85 to 89 37% among 90 to 94 48% among 95+ Dementia Illnesses and medications can produce depression & dementia-like syndromes Depression associated with cognitive abnormalities, can mimic or exacerbate dementia Initial depression may be first sign of difficultly for individual with early dementia The Impact of AD Once considered a rare disorder, Alzheimer s disease is now seen as a major public health problem that is seriously affecting millions of older Americans and their families Alzheimer s Disease (AD) Alzheimer's disease was the 6 th leading cause of death in 2010 Cost topped $172 billion in 2010 Expected to rise to well over $1 trillion in 2050, even without adjusting for inflation

4 What is AD? Alzheimer s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills Although the risk of developing AD increases with age in most people with AD, symptoms first appear after age 60 AD. It is caused by a fatal disease that affects the brain, not normal aging. What is AD? AD Statistics. AD is the most common cause of dementia among people age 65 and older Scientists estimate that around 4.5 million + Americans have AD For every 5-year age increase beyond 65, the percentage of people with AD doubles By 2050, 13.2 million older Americans expected to have AD if the current numbers hold and no preventive treatments become available Inside the Human Brain To understand Alzheimer s disease, it s important to know a bit about the brain Adult Brain s Vital Statistics Weight: 3 pounds Size: cauliflower 100 billion neurons 100 trillion synapses Inside the Human Brain Neurons The brain has billions of neurons, each with an axon and many dendrites To stay healthy, neurons must communicate with each other, carry out metabolism, and repair themselves AD disrupts all three of these essential jobs AD and the Brain Plaques and Tangles: The Hallmarks of AD The brains of people with AD have an abundance of two abnormal structures: Beta-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells Neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell AD and the Brain Pet Scan of Normal Brain The Changing Brain in Alzheimer s Disease No one knows what causes AD, but we do know a lot about what happens in the brain once AD takes hold Pet Scan of Alzheimer s Disease Brain AD plaque AD tangle

5 Risk Factors for AD AD and the Brain Known risk factors Aging Genetics/Family History Female gender Lack of education Possible risk factors Head trauma Depression Preclinical AD Signs of AD are first noticed in the entorhinal cortex, then proceed to the hippocampus Affected regions begin to shrink as nerve cells die Changes can begin years before symptoms appear Memory loss is often the first sign of AD *Down s syndrome 26 Early Warning Signs of AD Deterioration of ability to learn and retain new information (repeats questions) Difficulty with short-term memory (forgets recent conversations and events, misses appointments) Deterioration of ability to reason and carry out complex tasks (difficulties with job, handling finances) 7 Warning Signs of AD Asking the same question over and over again Repeating the same story again and again Forgetting how to cook, make repairs, or play cards activities that were previously done with ease and regularity Losing ability to pay bills or balance checkbook Lost in familiar surroundings, misplacing objects Neglecting to bathe, wearing same clothes over and over Relying on someone else (spouse) to make decisions or answer questions they previously would have handled themselves 28 AD and the Brain Mild to Moderate AD AD spreads through the brain. The cerebral cortex begins to shrink as more and more neurons stop working and die Mild AD signs can include memory loss, confusion, trouble handling money, poor judgment, mood changes, and increased anxiety Moderate AD signs can include increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements Changes in Mild AD Loses spark or zest for life - does not start anything Recent memory problems Loses judgment about money Has difficulty with new learning and making new memories Trouble finding words, may stop talking to avoid mistakes Shorter attention span, less motivation Easily loses way going to familiar places Resists change or new things Has trouble organizing and thinking logically Asks repetitive questions

6 Changes in Mild AD Withdraws, loses interest, is irritable, not as sensitive to others' feelings, uncharacteristically angry when frustrated or tired Won't make decisions, "I'll have what she is having" Takes longer to do routine chores and becomes upset if rushed or if something unexpected happens Forgets to pay, pays too much, or forgets how to pay Hands checkout person wallet instead of correct amount of money Forgets to eat, eats only one kind of food, or eats constantly Loses or misplaces things by hiding them in odd places or forgets where things go Constantly checks, searches or hoards things of no value Changes in Mild AD Memory loss in Alzheimer s not only affects new learning, but also results in gradual loss of knowledge structures and semantic memory stores Assessment of ADL s crucial to understand degree of patient s disability Enables realistic planning and interventions Bathing, dressing, toileting, transfer, continence, feeding, telephone, shopping, traveling, cooking, finances, medications, etc Changes in Moderate AD Changes in Moderate AD Apathy 72% Agitation 60% Anxiety 48% Irritability 42% Motor 38% Dysphoria 38% Disinhibition 36% Delusions 22% Changes in behavior, concern for appearance, hygiene, and sleep become more noticeable Mixes up identity of people Thinking a son is a brother or that a wife is a stranger Poor judgment creates safety issues when left alone Wanders and risks exposure, poisoning, falls, neglect, exploitation Trouble recognizing familiar people and own objects May take things that belong to others Continuously repeats stories, favorite words, statements, or motions like tearing tissues Has restless, repetitive movements in late afternoon or evening, such as pacing, trying doorknobs, fingering draperies Changes in Moderate AD Changes in Moderate AD Cannot organize thoughts or follow logical explanations Has trouble following written notes or completing tasks Makes up stories to fill in memory gaps. Might say, "Mama will come for me when she gets off work" May be able to read but cannot formulate the correct response to a written request May accuse, threaten, curse, fidget or behave inappropriately, such as kicking, hitting, biting, screaming or grabbing May become sloppy or forget manners May see, hear, smell, or taste things that are not there May accuse spouse of an affair, family of stealing Naps frequently, awakens at night believing time to go to work Difficulty positioning body to use the toilet or sit in a chair Needs help finding the toilet, using the shower, remembering to drink, and dressing for the weather or occasion May think mirror image is following him or television story is happening to her Exhibits inappropriate sexual behavior, such as mistaking another individual for a spouse Forgets what is private behavior and may disrobe in public

7 AD and the Brain Severe AD In severe AD, extreme shrinkage occurs in the brain. Patients are completely dependent on others for care Symptoms can include weight loss, seizures, skin infections, groaning, moaning, or grunting, increased sleeping, loss of bladder and bowel control Death usually occurs from aspiration pneumonia or other infections. Caregivers can turn to a hospice for help and palliative care 37 Changes in Severe AD Doesn't recognize self or close family Speaks in gibberish, is mute, or is difficult to understand May refuse to eat, chokes, or forgets to swallow May repetitively cry out, pat or touch everything Loses control of bowel and bladder Loses weight and skin becomes thin and tears easily Looks uncomfortable, cries out when moved or touched Forgets how to walk, too unsteady or weak to stand alone May have seizures, frequent infections, falls May groan, scream or mumble loudly Sleeps more Needs total assistance for all activities of daily living 38 Prognosis The course the disease takes and how fast changes occur vary from person to person On average, AD patients live from 8 to 10 years after they are diagnosed The disease can last for as many as 20 years Barriers to Early Diagnosis Misidentification by the family of early signs of AD as normal aging Denial and lack of insight by patient Reluctance to report symptoms (patient and caregiver) stigma Lack of definitive screening tools 39 AD Research: Diagnosing AD Experienced physicians in specialized AD centers can now diagnose AD with up to 90 percent accuracy. Early diagnosis has advantages: Doctors can rule out other conditions that may cause dementia If it is AD, families have more time to plan for the future Treatments can start earlier, when they may be more effective It helps scientists learn more about the causes and development of AD AD Research: Diagnosing AD Physicians today use a number of tools to diagnose AD: A detailed patient history Information from family and friends Physical and neurological exams and lab tests Neuropsychological tests Imaging tools such as CT scan, or magnetic resonance imaging (MRI). PET scans are used primarily for research purposes

8 AD Research: The Search for Causes Genetic Studies The two main types of AD are early-onset and late-onset: Early-onset AD is rare, usually affecting people aged 30 to 60 and usually running in families. Researchers have identified mutations in three genes that cause early-onset AD. Late-onset AD is more common. It usually affects people over age 65. Researchers have identified a gene that produces a protein called apolipoprotein E (ApoE). Scientists believe this protein is involved in the formation of beta-amyloid plaques. 43 AD Research: the Search for Causes Epidemiologic Studies Scientists examine characteristics, lifestyles, and disease rates of groups of people to gather clues about possible causes of AD. Researchers conduct yearly exams of physical and mental status, and studies of donated brains at autopsy. Mentally stimulating activity protects the brain in some ways 44 Treatment The Obama Administration's War on Alzheimer s Presidential advisory group set a goal to prevent and effectively treat Alzheimer s Disease by 2025 Treatment Scientists do not yet fully understand exactly how the medications work to treat AD Current research indicates acetylcholine-esterase inhibitors prevent the breakdown of acetylcholine, a brain chemical believed to be important for memory and thinking As AD progresses, the brain produces less and less acetylcholine and acetylcholine-esterase inhibitors may eventually lose their effect Treatment Treating the symptoms of AD can provide comfort, dignity, & independence for a longer period of time and can encourage and assist caregivers as well It is important to understand that none of these medications stops the disease itself Currently no approved therapies that can prevent, cure or even substantially slow the progression of dementia caused by AD Aricept (donepezil) Centrally acting, reversible acetylcholineesterase inhibitor Mild to moderate, perhaps moderate to severe Side effects include gastrointestinal upset Oral bioavailability of 100% Easily crosses the blood-brain barrier 1/2-life of about 70 hours = taken once a day

9 Namenda (memantine) N-methyl D-aspartate (NMDA) antagonist Delay progression of some of the symptoms of moderate to severe AD Allow patients to maintain certain daily functions a little longer ability to go to the bathroom independently for several more months, a benefit for both patients and caregivers Namenda (memantine) Believed to work by regulating glutamate, another important brain chemical that, when produced in excessive amounts, may lead to brain cell death Because NMDA antagonists work very differently from acetylcholine-esterase inhibitors, the two types of drugs can be prescribed in combination AD Research: the Search for New Treatments Researchers also are looking at other treatments, including: Cholesterol-lowering drugs called statins Anti-oxidants (vitamins) and folic acid Anti-inflammatory drugs Substances that prevent formation of beta-amyloid plaques Nerve growth factor to keep neurons healthy Research-Drugs The New England Journal Of Medicine Volume 366, March 8, 2012 Robert Howard, M.D.et al. Donepezil and Memantine for Moderate-to- Severe Alzheimer s Disease Research-Drugs 52 weeks long Pt swith Donepezil = MMSE points Pt swith Memantine= MMSE points Efficacy of donepezil and of memantinedid not differ significantly in the presence or absence of the other No significant benefits of donepezil and memantine over donepezil alone Research-Drugs AstraZeneca to proceed with Alzheimer's drug (01/12/2012) Phase II clinical trial, using the compound as an add-on treatment to donepezil (Aricept) in patients with mild to moderate Alzheimer s AstraZeneca's decision to invest further in the development of AZD1446 reflects well on the continued promise of research in Alzheimer s

10 Research-Drugs The Journal of Biological Chemistry. October 3, 2011 Computer simulations have shown how the active compounds and fragments of this disease-causing peptide interact with each other Researchers identified synthetic compounds (inhibitors) that interfere with the self-assembly of the amyloid beta peptide in vitro; they influence both early stages and the transition to the characteristic amyloid fibrils. On a theoretical level, these compounds thus satisfy an initial condition for the development of an Alzheimer drug Research-Imaging American Chemical Society 01/11/2012, ACS Medicinal Chemistry Letters No proven laboratory test or medical scan now exists for AD Development and initial laboratory tests of an imaging agent that shows promise for detecting the signs of AD in the brain, signs that now can't confirm a diagnosis until after patients have died New imaging agent (FPPDB), binds tightly to β-amyloid plaques and neurofibrillary tangles With further development, the imaging agent may allow early AD diagnosis in humans Research-Biomarkers Alliance for Aging Research, 01/04/2012 AD biomarkers -structural MRI, brain amyloid imaging and cerebrospinal fluid levels of amyloid beta-protein 42 (AB42) and tau Use in enrollment and as an outcome in AD clinical trials, along with current clinical assessments, such as neuropsychological testing and assessment of ADL s Those that identify the aspects of the molecular pathology of AD AB 42 and tau can be measured in cerebrospinal fluid Those that reflect the "downstream" consequences of that pathology MRI detects more "downstream" events that follow events initiated at the molecular level including neuronal loss and brain shrinkage caused by AD Must undergo validation and reliability studies in non-research settings before clinical utility in clinical practice can be determined Research-Lifestyle Washington University, St Louis, Missouri 201 cognitively normal adults aged 45 to 88 years More sedentary lifestyle was significantly associated with higher [ 11 C]PiBbinding for 4 carriers (P=.013) but not for noncarriers(p=.20) Cognitively normal sedentary APOE4 positive individuals may be at augmented risk for cerebral amyloid deposition Research-Lifestyle Sedentary lifestyle linked to greater cerebral amyloid, characteristic of AD, amongst cognitively normal individuals with the ε4 allele of the E (APOE) gene Patients with higher amounts of exercise had a lower average cortical PIB binding (binding potential values from the prefrontal cortex, gyrusrectus, lateral temporal, and precuneusregions), in comparison to patients who reported lower amounts of exercise. Findings also showed that ε4-positive participants had higher levels of cortical amyloid compared with those who were ε4- negative Research-Lifestyle Suggests that exercise at levels recommended by the American Heart Association may be particularly beneficial in reducing the risk of brain amyloid deposition in cognitively normal ε4-positive individuals

11 Managing Symptoms Agitation Common in AD, can be triggered by pain, medications, psychosocial stressors, etc. Psychosis Less common, increases as AD progresses Depression Present in approx. 40% of AD patients, often overlooked AD Research: Managing Symptoms Between 70 to 90% of people with AD eventually develop behavioral symptoms, including sleeplessness, wandering and pacing, aggression, agitation, anger, depression, and hallucinations and delusions. Experts suggest these general coping strategies for managing difficult Stay calm behaviors: and be understanding. Be patient & flexible. Don t argue or pressure. Acknowledge requests and respond to them. Try not to take behaviors personally. Remember: it s the disease talking, not your loved one. Experts encourage caregivers to try non-medical coping strategies first. However, medical treatment is often available if the behavior has become too difficult to handle. Researchers continue to look at both non-medical and medical ways to help caregivers Support for Caregivers Primarily spouses and daughters Physical & emotional health of caregiver is critical for optimal care of the patient Caregivers suffer from increased depression and physical illness, prescribed more medications Minimize caregiver distress and burden to defer institutionalization of the patient Thank You!