Dementia with Lewy Bodies

Victor W. Henderson, MD, MS Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences Stanford University Director, Stanford Alzheimer’s Disease Research Center

A Lewy body is an abnormal, round structure dementia, and here the pathological changes found inside nerve cells and composed largely are due to stroke and to related changes that of a protein called alpha-synuclein (Figure). impair blood circulation in the brain. DLB is Lewy bodies are associated with two the third most common cause. Changes of all important brain disorders, Parkinson's disease three disorders can occur in the same brain. and dementia with Lewy bodies (DLB). DLB Dementia can be defined as cognitive (mental) is classified as a neurodegenerative disease, decline that has an adverse impact on daily because it involves the progressive function or independence. The term mild impairment and loss of nerve cells. cognitive impairment is used to describe lesser cognitive decline that is not explained by age alone, but the decline does not impair daily function or affects function only minimally. Although DLB is a type of dementia, Lewy bodies can cause milder symptoms that might be better characterized as mild cognitive impairment.

Clinical criteria for dementia with Lewy bodies The dementia of DLB differs from that of Alzheimer's disease. In Alzheimer's disease, trouble remembering recent events is often an Figure. Cortical Lewy body. A single Lewy body (arrow) is shown within a pyramidal nerve cell in the early, prominent symptom. In DLB, memory cerebral cortex. H&E stain. Image courtesy of Dr. is often good early in the course of the illness. Edward D. Plowey, Stanford University. Instead, there can be confusion, mental

slowness, visual problems, trouble with spatial Dementia and mild cognitive relations, and difficulty with problem solving. impairment The Dementia with Lewy Bodies Consortium DLB is one of several causes of dementia. has recommended criteria for the diagnosis of The most common cause is Alzheimer's probable DLB (Table 1). The consortium disease, which is an entirely separate used the word "probable" to indicate that a neurodegenerative disease. Vascular dementia definite diagnosis of DLB usually requires is the second most common cause of documentation of Lewy bodies during a brain

Stanford ADRC | Page 1 | Supported by the NIH AG046366 V W Henderson / Dementia with Lewy Bodies autopsy. There are four "core features" of own and is occasionally seen with other brain DLB, and the diagnosis of DLB requires at disorders. least two of these features, plus dementia. DLB and Parkinson's disease overlap in One core feature is "fluctuating cognition." several ways, and the final core clinical This term refers to periods of confusion or feature of DLB is abnormal movement. In lack of alertness that come and go. A person Parkinson's disease, there are three cardinal with DLB may be drowsy off and on during types of abnormal movements, and any one of the daytime, stare off into space (zone out), or these qualifies as a core feature of DLB. speak in a disorganized manner. These three are bradykinesia (slowness), The second core feature is visual tremor (shaking), and rigidity (stiffness). hallucinations. These also come and go. Bradykinesia refers to slowness in facial Often, the hallucinations are of people or expression, moving the arms and legs, or animals. Even though these can be realistic, walking. It also refers to small movements, the patient sometimes knows quite well that such as separating the hands less than usual these cannot be real. when clapping. Another key feature is tremor, Although not a core feature, some people with especially when resting quietly and not DLB have other mental problems. These otherwise moving. The final key feature of include delusions (fixed, false beliefs like Parkinson's disease is stiffness, which is not paranoia), illusions (misperceptions), or a painful and contributes to slowness. To test false sense of presence or passage. (Presence for rigidity, the doctor might first ask the refers to the experience that someone is person to relax. The doctor should be able to nearby when no one is actually there. Passage move a relaxed arm or leg freely, with very refers to a fleeting, vague image of someone little resistance. When there is rigidity, the or something moving off to the side.) movement will feel stiff and have a ratchet quality. The third core feature is called REM sleep behavior disorder. REM stands for rapid eye Specialized laboratory tests can also be used movements, the stage of sleep during which to help meet consortium criteria for probable dreams occur. During REM sleep, only the DLB. eyes move; the arms and legs are still. In Table. Clinical criteria for probable dementia REM sleep behavior disorder, dreaming and with Lewy bodies staying still are disconnected. A person with A. Dementia, established by clinical examination this disorder will act out dreams and thrash B. Two or more of the following core features: about, and may even strike a bed partner. It is • Fluctuating cognition not uncommon for a spouse to move to a • Visual hallucinations separate bed to keep from being kicked or • REM sleep behavior disorder punched. Interestingly, REM sleep behavior • One or more cardinal feature of disorder sometimes appears years before other Parkinson's disease: bradykinesia problems of DLB. REM sleep behavior (slowness of movement), tremor at rest, or rigidity (stiffness) disorder is often associated with DLB or Parkinson's disease, but it can occur on its (after McKeith et al., 2017)

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Relation between DLB, will have mild movement symptoms, or none Parkinson's disease, and at all. Parkinson's disease dementia Evaluation and diagnosis DLB, Parkinson's disease, and Parkinson's disease dementia are closely related. In each, In most instances, a diagnosis of DLB is made the main problem is with alpha-synuclein. or confirmed by a neurologist, geriatrician, or This is a protein is found inside nerve cells at geriatric psychiatrist. A neurologist is best sites where one nerve cell communicates with qualified to recognize and diagnose other the next. In each disorder, alpha-synuclein neurological conditions causing dementia or clumps to form abnormal fibers and larger, affecting movement and mimicking DLB. round Lewy bodies. It is not known why The physician's evaluation is directed towards clumping takes place. These clumps affect documentation of dementia, looking for nerve cells in the brainstem (in an area called changes in movement, and determining the the substantia nigra), the cerebral cortex, and underlying cause. The assessment includes a certain other regions of the nervous system. careful medical, neurological, and psychiatric Nerve cells in the substantia nigra use history; a family history to see whether close dopamine as a chemical transmitter, and family members have a similar or related damage and death of the dopamine nerve cells disorder; a general physical examination; and cause movement symptoms of Parkinson's a neurological examination. The physician disease. The main symptoms of Parkinson's reviews the use of prescription and over-the- disease are bradykinesia, tremor, and rigidity. counter medications. Many older adults take Nerve cells in the cerebral cortex use different multiple drugs, some of which can cause chemical transmitters, and damage and death confusion, impair mental function, and affect of these nerve cells contribute to the mental movement. symptoms of DLB. Nerve cells in the The neurological examination includes substantia nigra and cerebral cortex can be assessment of bradykinesia, tremor, rigidity, affected more or less separately, or they can ataxia (poor coordination), and walking be affected at the same time. balance. Lewy body dementia The evaluation also includes a mental status Lewy body dementia (LBD) is an umbrella examination of memory and other cognitive term for both DLB and Parkinson's disease abilities, sometimes supplemented by more dementia. This term — LBD — is detailed testing by a neuropsychologist. The confusingly similar to DLB. When dementia physician should consider the possibility of occurs in someone who already has depression and look for evidence of anxiety. Parkinson's disease, physicians speak of Laboratory tests depend on the individual Parkinson's disease dementia. DLB is circumstances but usually include a screening diagnosed when dementia occurs before blood test for kidney, liver, and related movement symptoms of Parkinson's disease, metabolic functions; a blood test for thyroid or at the same time. Some people with DLB function; a blood test to determine the level of

Stanford ADRC | Page 3 | Supported by the NIH (AG047366) V W Henderson / Dementia with Lewy Bodies vitamin B12; and brain imaging. Brain Cardiac scintigraphy imaging with a CT (computed tomography) Parkinson's disease and DLB affect nerve cells scan or MRI (magnetic resonance imaging) outside the brain. 123Iodine- scan is used to evaluate brain structures and to metaiodobenzylguanidine (MIBG) is a help exclude stroke, tumor, and other less radioactively-labeled chemical. After it is common causes of dementia and abnormal injected into the blood, MIBG is stored in movement. None of these tests can prove the nerve cells that release norepinephrine. presence or absence of DLB. Norepinephrine, like dopamine, is a chemical messenger that travels a very short distance to Specialized laboratory tests activate a second nerve cell. In Parkinson's disease and DLB, the number of these second Specialized tests can help firm up a diagnosis nerve cells is often reduced in the heart. A of DLB when the extra information is needed scan (MIBG cardiac scintigraphy) showing for research. The Dementia with Lewy low levels of MIBG in the heart indicates a Bodies Consortium mentions tests that can be loss of nerve cells that receive norepinephrine. used to indicate a diagnosis of DLB (McKeith No laboratory test is perfect, and MIBG et al., 2017). These are a dopamine cardiac scintigraphy can be abnormal in transporter brain scan, a type of heart scan, certain other diseases and it is sometimes and a sleep study. Physicians typically do not normal in DLB. rely on these tests to diagnose DLB. Sleep study Dopamine transporter scan A sleep study test, also called PET (positron emission tomography) scans polysomnography, is done at a specialized provide images of the brain based on specific sleep center or in a hospital. Various molecules with radioactive labels. The recordings are done while falling asleep and dopamine transporter (DAT) is a protein throughout the night. The measurements molecule that helps move dopamine back into include brain waves (electroencephalogram), the nerve cell after this chemical messenger is oxygen level in the blood, heart rate, released. Nerve cells that use dopamine are breathing, and eye and leg movements. A lost in Parkinson's disease and DLB. In these sleep study that shows body movements disorders, DAT-PET usually shows low during REM sleep will confirm a diagnosis of dopamine transporter labeling in the putamen, REM sleep behavior disorder. REM sleep a brain area deep in the cerebral hemispheres. behavior disorder is one of the core features of This finding is not fully specific and can be DLB (Table). abnormal in other diseases that affect brain dopamine. Some patients with DLB will have a normal scan. Treatment and management DAT-SPECT (single photon emission There is not yet a cure for DLB. People with computed tomography) provides similar DLB can be helped by changes in their information, but brain details are clearer with environment, by lifestyle changes, and by PET than SPECT. prescription drugs.

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Environmental adjustments and lifestyle days each week. Exercise also helps changes depressive symptoms. Environmental adjustments help compensate Mental activity is potentially important. for declining mental abilities. A bulletin People obtain mental stimulation through board or white board, or a written or electronic social interactions, hobbies, card games and calendar can help some patients keep track of board games, and reading. There is no appointments and upcoming events. evidence that one form of mental stimulation Compartmentalized pill boxes can be used to — such as a set of computerized tasks — is organize medications. A person with better than another. dementia almost always requires help with Drug treatment more complex tasks like managing bills and finances, or simply maintaining a household. The Food and Drug Administration has not People with more severe dementia often need approved any drugs for the treatment of DLB. help with bathing, dressing, toileting, and One drug is approved for mild to moderate eating. dementia associated with Parkinson’s disease. Driving skills can deteriorate, and people with This is rivastigmine, a cholinesterase inhibitor, even mild dementia have a higher risk of which it is also approved for dementia due to accidents. In DLB, poor spatial skills and Alzheimer’s disease. This drug acts to fluctuating attention can affect driving safety. increase brain levels of acetylcholine (another In California, physicians are required by law chemical messenger between nerve cells). It to report a dementia diagnosis. The loss of a does not reverse or halt disease progression in driver's license is not automatic, however, and Parkinson's disease dementia or DLB, but it some people with mild dementia can retain can improve some of the symptoms. their licenses. Two other cholinesterase inhibitors are Reassurance, distraction, and redirection approved for use in Alzheimer’s disease sometimes help agitation or hallucinations or (donepezil and galantamine) but not delusions. Changing the environment to a specifically for Parkinson’s disease dementia more familiar, quieter, or less distracting or DLB. There is no evidence that one setting can help. People with dementia often cholinesterase inhibitor is more effective than benefit from a simpler, more peaceful, more another. These drugs are usually well structured daily routine. tolerated, but some people have loss of appetite, nausea, or diarrhea. Although the evidence for benefit is circumstantial, most physicians recommend The Food and Drug Administration has regular physical exercise, mental stimulation, approved pimavanserin for the treatment of social engagement, and good nutrition. Brisk hallucinations and delusions in the setting of walking and other forms of aerobic exercise psychosis in people with Parkinson’s disease. are usually recommended when there are no This approval does not extend to DLB. The health problems standing in the way. One Food and Drug Administration refers to target goal is to walk about 150 minutes each pimavanserin as an atypical antipsychotic. All week, divided into 30 minute intervals, five atypical antipsychotic drugs carry a warning

Stanford ADRC | Page 5 | Supported by the NIH (AG047366) V W Henderson / Dementia with Lewy Bodies of increased mortality (death) in people with prescription drugs, they can cause side effects, psychosis and dementia. This risk is rare. and they can be dangerous when taken with Quetiapine, another atypical antipsychotic other medicines. Most physicians advise drug, is often tried for mental symptoms in against these products. DLB that cannot be managed by environmental adjustments. It is not approved Reference by the Food and Drug Administration for this McKeith IG, Boeve BF, Dickson DW, et al. (2017) purpose either. Diagnosis and management of dementia with Lewy bodies. Neurology, 89, 88-100. People with DLB are very sensitive to antipsychotic drugs like haloperidol, Resources risperidone or olanzapine, which may increase confusion and increase motor symptoms of Alzheimer’s Association Parkinson’s disease, even at low doses. These www.alz.org drugs should be avoided. Lewy Body Dementia Association www.lbda.org/contact Other drugs can be used if there are problems with mood or disruptive behaviors. An National Institute on Aging, Alzheimer's Disease Centers antidepressant may help depression, even www.nia.nih.gov/research/dn/alzheimers- though it may have little or no effect on disease-centers cognitive impairment in DLB. National Institute on Aging, Lewy body A few people with dementia become agitated dementia or aggressive. These symptoms are www.nia.nih.gov/health/topics/lewy-body- sometimes triggered by a medical illness like a dementia bladder infection, by a medication side-effect, Stanford Alzheimer’s Disease Research or by a change in daily routine. It is important Center to search carefully for these underlying adrc.stanford.edu conditions. When no specific cause can be Stanford Center for Memory Disorders found and when agitation or aggression poses stanfordhealthcare.org/medical- a safety risk or is distressful to the patient, the clinics/memory-disorders-center.html physician may try other prescription Stanford Health Care Aging Adult Services medications for these symptoms. The stanfordhealthcare.org/medical-clinics/aging- concern, of course, is that other medications adult-services.html have potential side effects, as well. Some Stanford Movement Disorders Center drugs used for agitation can increase stanfordhealthcare.org/medical- confusion and risk of falling. clinics/movement-disorders-center.html

Patients and their families are sometimes tempted to try dietary supplements and herbal remedies. These alternative therapies have not undergone rigorous testing in humans, and © 2017 by Victor W. Henderson; all rights reserved. there is no evidence that they are effective. The author gives readers permission to download single Alternative therapies can be expensive. Like copies for nonexclusive, noncommercial use.

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