3Objectives Discuss early signs and symptoms of Alzheimer’s disease Discuss the difference between dementia typesBring up ways of initial evaluation and screening for cognitive impairment.Answer the question, “What can be done to slow down or prevent dementia?”Bring up current trends in dementia research
4Disclosures I’m not paid by any pharmaceutical company Some discussion is “off-label”Information presented is from multiple sources and is “evidence-based” – there are a lot of alternative treatments that do not have good trials to show if they are effective or not.
7Early Signs and Symptoms of Alzheimer’s Disease The Alzheimer’s Association talks about the 10 signs of Alzheimer’s disease1) Memory loss that disrupts daily life2) Challenges in planning or solvingproblems3) Difficulty completing familiar tasks
8Signs of Alzheimer’s4) Confusion with time or place 5) Trouble understanding visual images and spatial relationships 6) New problems with words in speaking or writing 7) Misplacing things and losing the ability to retrace steps
9Signs of Alzheimer’s8) Decreased or poor judgment 9) Withdrawal from work or social activities 10) Changes in mood and personality All of these can be signs of dementia, so what’s the difference?
10What is the Difference? Dementia Lewy-Body Frontotemporal Vascular ParkinsonsAlzheimer’s DiseaseotherDementia
13What is Dementia? Major impairment in learning and memory One of the following:Impairment in handling complex tasksImpairment in reasoning abilityImpaired spatial ability and orientationImpaired language
14What is Dementia?Impairments must significantly interfere with the individual’s work performance, usual social activities, or relationships with other peopleSignificant decline from previous level of functioningInsidious onset and progressive (Alzheimer’s)
15What is Dementia? Symptoms don’t occur exclusively during delirium Not better accounted for by another illnessDepressionHypothyroidismVitamin B12 deficiencyMedications or other substancesHydrocephalus or brain lesionEtc.
17The Three Main Stages of Dementia Mild or Early StageMemory loss and cognitive impairments are small but become increasingly noticeableThe person can cover up or make adjustments for these gaps and lapses, they continue to function independentlySigns and symptoms of this stage are often the result of stress or bereavement. In older people they may be the normal aging process
18The Three Main Stages of Dementia Moderate or Mild StageMemory lapses and confusion become more obvious and the person becomes more distressed by themThe person can no longer hide these from family and friendsTheir personality and mental abilities may start to change and physical problems developThe person needs more support to help them manage the tasks of daily of livingThey may need repeated reminders and help to eat, wash, dress, and use the toilet
19The Three Main Stages of Dementia Severe or Late StageIndividuals will become more severely disabled and need more help, gradually dependent on caregiversDementia may limit the person’s ability to communicateMemory and personality will deteriorate furtherThey will need more assistance with daily tasks of bathing, dressing and eating. They may no longer be able to live independently
21Alzheimer’sHallmark of Alzheimer’s is slow start with gradual progression over yearsIt is diagnosed by talking with the person and the family/friendsThere is no blood test or study (MRI, etc.) that confirms Alzheimer’s, these rule out other causesThe only definitive diagnosis has been brain biopsy
22Dementia with Lewy bodies Fluctuations – often look like a strokeVisual hallucinationsParkinson’s-like features
23Vascular Dementia Dementia Often step-wise after strokes or TIA’s May be silent, but a brain scan (CT, MRI) shows many small areas of strokeOften can be “mixed” with Alzheimer’s
24Parkinson’s Dementia Dementia Associated with more severe Parkinson’s diseaseDiffers from Lewy Body dementiaOften functional decline from Parkinson’s is much more significant than the “thinking” problems
25Frontotemporal Dementia Personality changesLack of insightSocially inappropriateLoss of empathyMental rigidity
26What about Mild Cognitive Impairment? (MCI) Memory difficulties but no problems with ability to function in daily lifeVery common pre-cursor to dementiaThis is where treatments have found the best benefit to delay rapid decline
28Early Detection Short term memory loss, i.e. frequent “senior moments” Avoiding activities that were normally commonProblems with finances, getting lost, leaving the stove on, etc.Wearing the same clothes and forgetting to changePoor decision making – prone to financial abuse
29Tools for Screening Saint Louis University Mental Status Exam (SLUMS) Mini Mental Status Exam (MMSE)Alzheimer’s Association Early Identification ToolsMemory Impairment Screen (MIS)Mini-CogGeneral Practitioner Assessment of Cognition (GPCOG)Geriatric Depression Scale (GDS)
30Summary of Screening SLUMS – 8 minutes, free, has scoring for MCI MMSE – 8 minutes – cost money, less specific for MCIMIS – less than 5 minutes – simple scoring, all verbalGPCOG – less than 5 minutes – uses informant to help with half the testMini-Cog – less than 5 minutes – very simple screen with 2 components
31Testing for cognitive impairment Patient and family interviewPhysical ExamMental Status and depression assessmentLabs: CBC, Glucose, serum electrolytes, BUN/creatinine, TSH, Drug levels (e.g. digoxin), liver function tests, B12 and folate levels, VDRL, CalciumCT scanning without IV contrast – detects hydrocephalus, mass lesions, ischemic changes
32What Can We Do? Antioxidant vitamins (E, C, A) - don’t help growing number of studies show thisVitamins B6, B12, folate – only help if deficientVitamin D – may help a littleFish oil (omega-3 fatty acids) – may have some benefit, still in trials, several negative trials outGinkgo Biloba – doesn’t helpNutriceuticals – see magazines and newspaper ads – lack evidence, often financial scams
33Current Medical Treatments Helps a little, only at higher dosesEarly treatment more promisingOnly 5 medications in 2 classes that are FDA approvedDelays, doesn’t preventNot very effective in moderate to severe dementiaOften the side effects are limiting
34FDA Approved Medications Cholinesterase Inhibitors* tacrine (Cognex) - * no longer availablegalantamine (Razadyne and Razadyne ER)donepezil (Aricept)rivastigmine (Exelon and Exelon Patch)N-methyl-D-asparate (NMDA) receptor antagonistmemantine (Namenda and Namenda XR)
36Current Trends in Dementia Research Biomarkers for early detectionBrain imagingBody proteinsGenetic risk profilingFocus on mild cognitive impairmentFuture Drugs
37Biomarkers for Early Detection Current diagnosis of Alzheimer's relies largely on documenting mental decline. We now know that Alzheimer's has already caused severe brain damage in individuals who meet the criteria for mental decline.Researchers hope to discover an easy and accurate way to detect Alzheimer's before these devastating symptoms begin. Experts believe that biomarkers (short for "biological markers") offer one of the most promising paths. Biomarkers are reliable predictors and indicators of a disease process. Biomarkers include proteins in blood or spinal fluid, genetic variations (mutations) or brain changes detectable by imaging.
38Brain Imaging for Early Detection Structural Imagingprovides information about the shape, position or volume of brain tissue. Structural techniques include magnetic resonance imaging (MRI) and computed tomography (CT)Functional Imagingreveals how well cells in various brain regions are working by showing how actively the cells use sugar or oxygen. Functional techniques include positron emission tomography (PET) and functional MRI (fMRI)Molecular Imaging Technologies – looks at beta amyloid deposits during PET scanuses highly targeted radiotracers to detect cellular or chemical changes linked to specific diseases. Molecular imaging technologies include PET, fMRI and single photon emission computed tomography (SPECT). i.e. Pittsburgh compound B (PIB), 18F flutemetamol (flute), Florbetapir F 18 (18F-AV-45), Florbetaben (BAY )
40Body Protein Analysis Cerebrospinal fluid (CSF) proteins Research suggests that Alzheimer's disease in its earliest stages may cause changes in CSF levels of tau and beta-amyloid, two proteins that form abnormal brain deposits strongly linked to the disease.Unfortunately, there is a lack of consistency from lab to lab that makes this unreliableProteins in blood or other parts of the bodyStill in speculation
41Genetic Risk Profiling Scientists have identified three genes with rare variations that cause Alzheimer's and several genes that increase risk but don't guarantee that a person will develop the disease. Investigators worldwide are working to find additional risk genes. As more effective treatments are developed, genetic profiling may become a valuable risk assessment tool for wider use.
42Genetic Testing for APO-e4 The strongest risk geneIncluded in some clinical trials to identify participants at high risk for the diseaseAPOE-e4 testing is not currently recommended outside research settings because there are no treatments yet available that can change the course of Alzheimer's
43Focus On Mild Cognitive Impairment Increased risk of developing Alzheimer's disease within a few years; research surrounding MCI offers another potential path to earlier diagnosis.Individuals with MCI have a problem with memory or another mental function serious enough to be noticeable to themselves and those close to them and to show up on mental status testing. These problems, however, are not severe enough to interfere with daily activities, so the person does not meet current diagnostic guidelines for Alzheimer's.While individuals with MCI often go on to develop Alzheimer's disease, this is not always the case. In some people, MCI never gets worse. In others, it eventually gets better.
44Targets for Future Drugs Beta-amyloidTau proteinInflammationInsulin resistanceGauging treatment impact with brain imaging and biomarkersLearning from families with rare Alzheimer-causing genetic changes
46Beta-Amyloid Drug Research The chief component of plaques, one hallmark Alzheimer's brain abnormalityThis protein fragment is clipped from its parent compound amyloid precursor protein (APP) by two enzymes — beta-secretase and gamma-secretaseResearchers are developing medications aimed at virtually every point in amyloid processingBlocking activity of both enzymesPreventing the beta-amyloid fragments from clumping into plaquesUsing antibodies against beta-amyloid to clear it from the brain
47Tau Protein Drug Research The chief component of tangles, the other hallmark brain abnormalityResearchers are investigating strategies to keep tau molecules from collapsing and twisting into tangles, a process that destroys a vital cell transport system.
48Inflammation Drug Research Key Alzheimer's brain abnormalityScientists have learned a great deal about molecules involved in the body's overall inflammatory response and are working to better understand specific aspects of inflammation most active in the brain.These insights may point to novel anti-inflammatory treatments for Alzheimer's disease.
49Insulin Resistance Drug Research Insulin may be linked to Alzheimer's diseaseResearchers are exploring the role of insulin in the brain and closely related questions of how brain cells use sugar and produce energyThese investigations may reveal strategies to support cell function and stave off Alzheimer-related changes
50Gauging Treatment Impact with Brain Imaging and Biomarkers Many clinical trials in progress include various brain imaging studies and testing of blood or spinal fluidResearchers hope these techniques will one day provide methods to diagnose Alzheimer's disease in its earliest, most treatable stages — possibly even before symptoms appearBiomarkers may also eventually offer better methods to monitor response to treatment
51Learning from families with rare Alzheimer-causing genetic changes Another new approach to testing experimental drugs to be given before symptoms appear focuses on individuals with rare genetic mutations that guarantee they'll eventually develop Alzheimer's diseaseAll of these currently known mutations affect beta-amyloid processing or production
52Important Points Alzheimer’s disease is best treated when caught early Alzheimer’s affects more than memoryAlzheimer’s is the most common kind of dementiaHealthy living (diet, exercise, avoiding bad stuff, taking care of medical problems) is the best way to prevent dementia
53Important PointsThere are few current medical treatments for Alzheimer’s that have modest successThere are lots of areas of research in Alzheimer’s that look promisingEarly detection works best for all facets of this disease!
55ReferencesAlzheimer’s Association website (www.alz.org) and research centerDrug Utilization in Practice October 2013 “Ginkgo Biloba for Memory”Journal of Alzheimer’s & Dementia 17 Dec “Alzheimer’s Association Recommendations for operationalizing the detection of cognitive impairment during the Medicare Annual Wellness Visit in a primary care setting”UptoDateTreatment of dementiaCholinesterase inhibitors in the treatment of dementiaGenetics of Alzheimer diseaseRisk factors for dementiaClinical manifestations and diagnosis of Alzheimer diseaseEvaluation of cognitive impairment and dementiaPrevention of dementiaClinical features and diagnosis of dementia with Lewy bodiesFrontotemporal dementia: Clinical features and diagnosisParkinson disease dementia