Current Trends in Alzheimer’s Disease Brian Quinn DO Geriatrics, Hospice and Palliative Care

Objectives Discuss early signs and symptoms of Alzheimer’s disease Discuss the difference between dementia types Bring 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

Disclosures 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.

Early Signs and Symptoms of Alzheimer’s Disease The Alzheimer’s Association talks about the 10 signs of Alzheimer’s disease 1) Memory loss that disrupts daily life 2) Challenges in planning or solving problems 3) Difficulty completing familiar tasks

Signs of Alzheimer’s 4) 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

Signs of Alzheimer’s 8) 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?

What is the Difference? Dementia Lewy-Body Frontotemporal Vascular Parkinsons Alzheimer’s Disease other Dementia

What is Dementia? Major impairment in learning and memory One of the following: Impairment in handling complex tasks Impairment in reasoning ability Impaired spatial ability and orientation Impaired language

What is Dementia? Impairments must significantly interfere with the individual’s work performance, usual social activities, or relationships with other people Significant decline from previous level of functioning Insidious onset and progressive (Alzheimer’s)

What is Dementia? Symptoms don’t occur exclusively during delirium Not better accounted for by another illness Depression Hypothyroidism Vitamin B12 deficiency Medications or other substances Hydrocephalus or brain lesion Etc.

The Three Main Stages of Dementia Mild or Early Stage Memory loss and cognitive impairments are small but become increasingly noticeable The person can cover up or make adjustments for these gaps and lapses, they continue to function independently Signs and symptoms of this stage are often the result of stress or bereavement. In older people they may be the normal aging process

The Three Main Stages of Dementia Moderate or Mild Stage Memory lapses and confusion become more obvious and the person becomes more distressed by them The person can no longer hide these from family and friends Their personality and mental abilities may start to change and physical problems develop The person needs more support to help them manage the tasks of daily of living They may need repeated reminders and help to eat, wash, dress, and use the toilet

The Three Main Stages of Dementia Severe or Late Stage Individuals will become more severely disabled and need more help, gradually dependent on caregivers Dementia may limit the person’s ability to communicate Memory and personality will deteriorate further They will need more assistance with daily tasks of bathing, dressing and eating. They may no longer be able to live independently

Types of Dementia Alzheimer’s disease 60 - 80 % Lewy Body dementia 10 – 15 % Vascular dementia 5 - 10 % Parkinson’s dementia 5 - 8 % Frontotemporal dementia 2 – 5 % Other < 2 % (alcohol, Pick’s disease, MS, etc.)

Alzheimer’s Hallmark of Alzheimer’s is slow start with gradual progression over years It is diagnosed by talking with the person and the family/friends There is no blood test or study (MRI, etc.) that confirms Alzheimer’s, these rule out other causes The only definitive diagnosis has been brain biopsy

Dementia with Lewy bodies Fluctuations – often look like a stroke Visual hallucinations Parkinson’s-like features

Vascular Dementia Dementia Often step-wise after strokes or TIA’s May be silent, but a brain scan (CT, MRI) shows many small areas of stroke Often can be “mixed” with Alzheimer’s

Parkinson’s Dementia Dementia Associated with more severe Parkinson’s disease Differs from Lewy Body dementia Often functional decline from Parkinson’s is much more significant than the “thinking” problems

Frontotemporal Dementia Personality changes Lack of insight Socially inappropriate Loss of empathy Mental rigidity

What about Mild Cognitive Impairment? (MCI) Memory difficulties but no problems with ability to function in daily life Very common pre-cursor to dementia This is where treatments have found the best benefit to delay rapid decline

Why is early detection important?

Early Detection Short term memory loss, i.e. frequent “senior moments” Avoiding activities that were normally common Problems with finances, getting lost, leaving the stove on, etc. Wearing the same clothes and forgetting to change Poor decision making – prone to financial abuse

Tools for Screening Saint Louis University Mental Status Exam (SLUMS) Mini Mental Status Exam (MMSE) Alzheimer’s Association Early Identification Tools Memory Impairment Screen (MIS) Mini-Cog General Practitioner Assessment of Cognition (GPCOG) Geriatric Depression Scale (GDS)

Summary of Screening SLUMS – 8 minutes, free, has scoring for MCI MMSE – 8 minutes – cost money, less specific for MCI MIS – less than 5 minutes – simple scoring, all verbal GPCOG – less than 5 minutes – uses informant to help with half the test Mini-Cog – less than 5 minutes – very simple screen with 2 components

Testing for cognitive impairment Patient and family interview Physical Exam Mental Status and depression assessment Labs: CBC, Glucose, serum electrolytes, BUN/creatinine, TSH, Drug levels (e.g. digoxin), liver function tests, B12 and folate levels, VDRL, Calcium CT scanning without IV contrast – detects hydrocephalus, mass lesions, ischemic changes

What Can We Do? Antioxidant vitamins (E, C, A) - don’t help growing number of studies show this Vitamins B6, B12, folate – only help if deficient Vitamin D – may help a little Fish oil (omega-3 fatty acids) – may have some benefit, still in trials, several negative trials out Ginkgo Biloba – doesn’t help Nutriceuticals – see magazines and newspaper ads – lack evidence, often financial scams

Current Medical Treatments Helps a little, only at higher doses Early treatment more promising Only 5 medications in 2 classes that are FDA approved Delays, doesn’t prevent Not very effective in moderate to severe dementia Often the side effects are limiting

FDA Approved Medications Cholinesterase Inhibitors * tacrine (Cognex) - * no longer available galantamine (Razadyne and Razadyne ER) donepezil (Aricept) rivastigmine (Exelon and Exelon Patch) N-methyl-D-asparate (NMDA) receptor antagonist memantine (Namenda and Namenda XR)

Current Trends in Dementia Research Biomarkers for early detection Brain imaging Body proteins Genetic risk profiling Focus on mild cognitive impairment Future Drugs

Biomarkers 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.

Brain Imaging for Early Detection Structural Imaging provides information about the shape, position or volume of brain tissue. Structural techniques include magnetic resonance imaging (MRI) and computed tomography (CT) Functional Imaging reveals 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 scan uses 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 94-9172)

PET scan

Body 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 unreliable Proteins in blood or other parts of the body Still in speculation

Genetic 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.

Genetic Testing for APO-e4 The strongest risk gene Included in some clinical trials to identify participants at high risk for the disease APOE-e4 testing is not currently recommended outside research settings because there are no treatments yet available that can change the course of Alzheimer's

Focus 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.

Targets for Future Drugs Beta-amyloid Tau protein Inflammation Insulin resistance Gauging treatment impact with brain imaging and biomarkers Learning from families with rare Alzheimer-causing genetic changes

Beta-Amyloid Drug Research The chief component of plaques, one hallmark Alzheimer's brain abnormality This protein fragment is clipped from its parent compound amyloid precursor protein (APP) by two enzymes — beta-secretase and gamma-secretase Researchers are developing medications aimed at virtually every point in amyloid processing Blocking activity of both enzymes Preventing the beta-amyloid fragments from clumping into plaques Using antibodies against beta-amyloid to clear it from the brain

Tau Protein Drug Research The chief component of tangles, the other hallmark brain abnormality Researchers are investigating strategies to keep tau molecules from collapsing and twisting into tangles, a process that destroys a vital cell transport system.

Inflammation Drug Research Key Alzheimer's brain abnormality Scientists 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.

Insulin Resistance Drug Research Insulin may be linked to Alzheimer's disease Researchers are exploring the role of insulin in the brain and closely related questions of how brain cells use sugar and produce energy These investigations may reveal strategies to support cell function and stave off Alzheimer-related changes

Gauging Treatment Impact with Brain Imaging and Biomarkers Many clinical trials in progress include various brain imaging studies and testing of blood or spinal fluid Researchers hope these techniques will one day provide methods to diagnose Alzheimer's disease in its earliest, most treatable stages — possibly even before symptoms appear Biomarkers may also eventually offer better methods to monitor response to treatment

Learning 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 disease All of these currently known mutations affect beta-amyloid processing or production

Important Points Alzheimer’s disease is best treated when caught early Alzheimer’s affects more than memory Alzheimer’s is the most common kind of dementia Healthy living (diet, exercise, avoiding bad stuff, taking care of medical problems) is the best way to prevent dementia

Important Points There are few current medical treatments for Alzheimer’s that have modest success There are lots of areas of research in Alzheimer’s that look promising Early detection works best for all facets of this disease!

Questions? ????

References Alzheimer’s Association website (www.alz.org) and research center Drug Utilization in Practice October 2013 “Ginkgo Biloba for Memory” Journal of Alzheimer’s & Dementia 17 Dec 2012 “Alzheimer’s Association Recommendations for operationalizing the detection of cognitive impairment during the Medicare Annual Wellness Visit in a primary care setting” UptoDate Treatment of dementia Cholinesterase inhibitors in the treatment of dementia Genetics of Alzheimer disease Risk factors for dementia Clinical manifestations and diagnosis of Alzheimer disease Evaluation of cognitive impairment and dementia Prevention of dementia Clinical features and diagnosis of dementia with Lewy bodies Frontotemporal dementia: Clinical features and diagnosis Parkinson disease dementia

Thank you!