Lewy Body Dementia
Disease Details
Family Health Simplified
- Description
- Lewy body dementia is a progressive neurological disorder characterized by abnormal deposits of alpha-synuclein protein in the brain, leading to cognitive decline, visual hallucinations, and motor symptoms similar to Parkinson's disease.
- Type
- Lewy body dementia is a type of progressive brain disorder that affects thinking, memory, and movement control. It is generally not considered to be inherited in a straightforward Mendelian fashion, meaning it does not typically follow a simple genetic transmission pattern. While most cases are sporadic, some instances may have a familial component, potentially involving a combination of genetic and environmental factors.
- Signs And Symptoms
- DLB is dementia that occurs with "some combination of fluctuating cognition, recurrent visual hallucinations, rapid eye movement (REM) sleep behavior disorder (RBD), and parkinsonism", according to Armstrong (2019), when Parkinson's disease is not well established before the dementia occurs. DLB has widely varying symptoms and is more complex than many other dementias. Several areas of the nervous system (such as the autonomic nervous system and numerous regions of the brain) can be affected by Lewy pathology, in which the alpha-synuclein deposits cause damage and corresponding neurologic deficits.In DLB, there is an identifiable set of early signs and symptoms; these are called the prodromal, or pre-dementia, phase of the disease. These early signs and symptoms can appear 15 years or more before dementia develops. The earliest symptoms are constipation and dizziness from autonomic dysfunction, hyposmia (reduced ability to smell), RBD, anxiety, and depression. RBD may appear years or decades before other symptoms. Memory loss is not always an early symptom.Manifestations of DLB can be divided into essential, core, and supportive features. Dementia is the essential feature and must be present for diagnosis, while core and supportive features are further evidence in support of diagnosis (see diagnostic criteria below).
- Prognosis
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As of 2021, no cure is known for DLB. The prognosis for DLB has not been well studied; early studies had methodological limitations, such as small sample size and selection bias. Relative to AD and other dementias, DLB generally leads to higher rates of disability, hospitalization and institutionalization, and lower life expectancy and quality of life, with increased costs of care. Depression, apathy, and visual hallucinations contribute to the reduced quality of life. Decline may be more rapid when the APOE gene is present, or when AD—or its biomarkers—is also present. The severity of orthostatic hypotension also predicts a worse prognosis. Visuospatial deficits early in the course of DLB were thought to be a predictor of rapid decline, but more recent studies did not find an association.The trajectory of cognitive decline in DLB is difficult to establish because of the high rate of missed diagnoses; the typical delay of a year in the US, and 1.2 years in the UK, for diagnosis of DLB mean that a baseline from which deterioration can be measured is often absent. Compared to AD, which is better studied, memory is thought to be retained longer, while verbal fluency may be lost faster, but the most common tools used to assess cognition may miss the most common cognitive deficits in DLB, and better studies are needed.
There are more neuropsychiatric symptoms in DLB than AD, and they may emerge earlier, so those with DLB may have a less favorable prognosis, with more rapid cognitive decline, more admissions to residential care, and a lower life expectancy. An increased rate of hospitalization compared to AD is most commonly related to hallucinations and confusion, followed by falls and infection.Life expectancy is difficult to predict, and limited study data are available. Survival may be defined from the point of disease onset, or from the point of diagnosis. There is wide variability in survival times, as DLB may be rapidly or slowly progressing. A 2019 meta-analysis found an average survival time after diagnosis of 4.1 years—indicating survival in DLB 1.6 years less than after a diagnosis of Alzheimer's. A 2017 review found survival from disease onset between 5.5 and 7.7 years, and survival from diagnosis between 1.9 and 6.3 years. The difference in survival between AD and DLB could be because DLB is harder to diagnose, and may be diagnosed later in the course of the disease. An online survey with 658 respondents found that, after diagnosis, more than 10% died within a year, 10% lived more than 7 years, and some live more than 10 years; some people with Lewy body dementias live for 20 years. Shorter life expectancy is more likely when visual hallucinations, abnormal gait, and variable cognition are present early on.Fear and anxiety feature strongly for both people with Lewy body dementia and their caregivers; a range of emotional responses to living with Lewy bodies includes fear of hallucinations, fear of falls and frightening nightmares as a result of RBD, and being fearful of the effects of tiredness and fatigue. The symptoms of fluctuations, depression, delirium and violence are also experienced as frightening. An immense amount of physical support from friends and family is often required to maintain social and supporting relationships. Individuals with Lewy body dementias describe feeling a burden in the wider social context, as they reduce attending social events due to their increasing physical needs. Frequently reported burden dimensions include personal strain and interference with personal life, which can lead to relationship dissatisfaction and resentment.In the late phase of the disease, people may be unable to care for themselves. Falls—caused by many factors including parkinsonism, dysautonomia, and frailness—increase morbidity and mortality. Failure to thrive and aspiration pneumonia, a complication of dysphagia (difficulty swallowing) that results from dysautonomia, commonly cause death among people with the Lewy body dementias. Cardiovascular disease and sepsis are also common causes of death. - Onset
- Lewy body dementia (LBD) typically has an onset in people who are over the age of 50, but it can occur earlier in rare cases. Onset is often gradual, with symptoms worsening over time. Specific early symptoms may include cognitive decline, visual hallucinations, and motor symptoms similar to Parkinson's disease.
- Prevalence
- The prevalence of Lewy body dementia (LBD) varies, but it is estimated to affect approximately 1.4 million people in the United States. It is the second most common type of progressive dementia after Alzheimer's disease, accounting for about 5% to 10% of dementia cases overall.
- Epidemiology
- The Lewy body dementias are as a group the second most common form of neurodegenerative dementia after AD as of 2021. DLB itself is one of the three most common types of dementia, along with AD and vascular dementia.The diagnostic criteria for DLB before 2017 were highly specific, but not very sensitive, so that more than half of cases were missed historically. Dementia with Lewy bodies was under-recognized as of 2021, and there is little data on its epidemiology. The incidence and prevalence of DLB are not known accurately, but estimates are increasing with better recognition of the condition since 2017.About 0.4% of those over the age of 65 are affected with DLB, and between 1 and 4 per 1,000 people develop the condition each year. Symptoms usually appear between the ages of 50 and 80 (median 76), and it is not uncommon for it to be diagnosed before the age of 65.DLB is thought to be slightly more common in men than women, but this finding has been challenged and is inconsistent across studies. Women may be over-represented in community samples and under-represented in clinical populations, where RBD is more frequently diagnosed in men; the diagnosis appears to have a higher prevalence for men in those under 75, while women appear to be diagnosed later and with greater cognitive impairment. Studies in Japan, France and Britain show a more equal prevalence between men and women than in the US.An estimated 10 to 15% of diagnosed dementias are Lewy body type, but estimates range as high as 23% for those in clinical studies. A French study found an incidence among persons 65 years and older almost four times higher than a US study (32 US vs 112 France per 100,000 person-years), but the US study may have excluded people with only mild or no parkinsonism, while the French study screened for parkinsonism. Neither of the studies assessed systematically for RBD, so DLB may have been underdiagnosed in both studies. A door-to-door study in Japan found a prevalence of 0.53% for persons 65 and older, and a Spanish study found similar results.
- Intractability
- Lewy body dementia (LBD) is considered intractable because it currently has no cure and is progressively debilitating. Management focuses on alleviating symptoms and improving quality of life through medications and supportive therapies.
- Disease Severity
- Lewy body dementia (LBD) is a progressive and significant disorder that can range from mild to severe. It typically impairs cognitive functions, causing marked declines in thinking, memory, and movement abilities. Symptoms often worsen over time, significantly affecting daily activities and quality of life.
- Healthcare Professionals
- Disease Ontology ID - DOID:12217
- Pathophysiology
- DLB is characterized by the development of abnormal collections of alpha-synuclein protein within diseased brain neurons, manifesting as Lewy bodies and Lewy neurites. When these clumps of protein form, neurons function less optimally and eventually die. Neuronal loss in DLB leads to profound dopamine dysfunction and marked cholinergic pathology; other neurotransmitters might be affected, but less is known about them. Damage in the brain is widespread, and affects many domains of functioning. Loss of acetylcholine-producing neurons is thought to account for degeneration in memory and learning, while the death of dopamine-producing neurons appears to be responsible for degeneration of behavior, cognition, mood, movement, motivation, and sleep. The extent of Lewy body neuronal damage is a key determinant of dementia in the Lewy body disorders.The precise mechanisms contributing to DLB are not well understood and are a matter of some controversy. The role of alpha-synuclein deposits is unclear, because individuals with no signs of DLB have been found on autopsy to have advanced alpha-synuclein pathology. The relationship between Lewy pathology and widespread cell death is contentious. It is not known if the pathology spreads between cells or follows another pattern. The mechanisms that contribute to cell death, how the disease advances through the brain, and the timing of cognitive decline are all poorly understood. There is no model to account for the specific neurons and brain regions that are affected.Autopsy studies and amyloid imaging studies using Pittsburgh compound B (PiB) indicate that tau protein pathology and amyloid plaques, which are hallmarks of AD, are also common in DLB and more common than in Parkinson's disease dementia. Amyloid-beta (Aβ) deposits are found in the tauopathies—neurodegenerative diseases characterized by neurofibrillary tangles of hyperphosphorylated tau protein—but the mechanism underlying dementia is often mixed, and Aβ is also a factor in DLB.A proposed pathophysiology for RBD implicates neurons in the reticular formation that regulate REM sleep. RBD might appear decades earlier than other symptoms in the Lewy body dementias because these cells are affected earlier, before spreading to other brain regions.
- Carrier Status
- Lewy body dementia is not typically considered a genetic disorder in the same way as conditions like cystic fibrosis or Huntington's disease. Therefore, there is no carrier status associated with it. Most cases of Lewy body dementia are sporadic, meaning they occur in individuals with no clear family history. However, in some rare instances, there may be a genetic component or a higher familial risk associated with certain genetic mutations. If you have specific genetic concerns, consulting a genetic counselor or healthcare professional can provide more personalized information.
- Mechanism
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Lewy body dementia (LBD) is a neurodegenerative disease characterized by the abnormal accumulation of a protein called alpha-synuclein in the brain. These protein deposits, known as Lewy bodies, primarily affect cognitive and motor functions.
**Mechanism:**
The exact mechanism behind Lewy body dementia is not fully understood, but it involves the widespread formation of Lewy bodies within neurons. Lewy bodies disrupt normal cellular functions, leading to neuronal cell death and the subsequent symptoms of dementia. Affected brain regions typically include the cerebral cortex, limbic system, and substantia nigra, which are involved in cognitive processes, emotion, and movement control.
**Molecular Mechanisms:**
1. **Alpha-Synuclein Aggregation:** Alpha-synuclein is a protein normally implicated in synaptic vesicle regulation. In LBD, this protein misfolds and aggregates into insoluble fibrils that form Lewy bodies.
2. **Proteasome Dysfunction:** The ubiquitin-proteasome system, responsible for degrading misfolded or damaged proteins, is compromised in LBD, leading to the accumulation of alpha-synuclein and other toxic proteins.
3. **Mitochondrial Dysfunction:** Abnormal alpha-synuclein aggregates can impair mitochondrial function, leading to reduced energy production and increased oxidative stress.
4. **Cell-to-Cell Spread:** Misfolded alpha-synuclein may propagate from cell to cell, facilitating the spread of Lewy body pathology throughout the brain.
5. **Neuroinflammation:** Chronic inflammation and activation of microglia (the brain's immune cells) are associated with the neurodegenerative process in LBD. This inflammation can further exacerbate neuronal damage.
These molecular mechanisms interact in complex ways to drive the progression of Lewy body dementia, contributing to the clinical symptoms observed in affected individuals. - Treatment
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Lewy body dementia (LBD) treatment primarily focuses on managing symptoms:
1. **Medications:**
- **Cholinesterase inhibitors:** Improve cognitive functioning and behavioral symptoms by increasing levels of neurotransmitters in the brain.
- **Levodopa:** Treats movement symptoms but may increase hallucinations.
- **Antipsychotics:** Used with caution due to severe sensitivity and potential worsening of symptoms.
- **Antidepressants:** Manage depressive symptoms.
2. **Non-pharmacological Interventions:**
- **Physical therapy:** Improves mobility and reduces fall risk.
- **Occupational therapy:** Enhances the ability to perform daily activities.
- **Cognitive therapies:** Maintain cognitive function and manage behavioral issues.
3. **Lifestyle and Supportive Therapies:**
- **Healthy diet and regular physical activity:** Support overall health.
- **Structured routines and environmental modifications:** Reduce confusion and agitation.
- **Support groups and counseling:** Benefit both patients and caregivers.
Careful monitoring and individualized treatment plans are crucial due to varying symptoms and disease progression. - Compassionate Use Treatment
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Compassionate use treatments and off-label or experimental treatments for Lewy Body Dementia (LBD) include several approaches:
1. **Neflamapimod**: This drug is being investigated for its potential to improve cognitive function and reduce inflammation in the brain.
2. **Anavex 2-73 (Blarcamesine)**: An investigational drug aiming to modify the disease process and improve both cognitive and motor functions.
3. **Ambroxol**: Originally a respiratory medication, it's being explored for its ability to increase GCase enzyme activity, affecting alpha-synuclein buildup.
4. **Rivastigmine**: Although primarily an Alzheimer's disease treatment, it's used off-label to manage cognitive symptoms in LBD.
5. **Memantine**: Another Alzheimer's medication used off-label to help with cognition and potentially reduce hallucinations and agitation in LBD patients.
6. **Nuplazid (Pimavanserin)**: Approved for Parkinson’s disease psychosis, it is sometimes used off-label for similar symptoms in LBD.
7. **Deep Brain Stimulation (DBS)**: While primarily for Parkinson’s disease, it is being explored experimentally to alleviate motor symptoms in LBD.
Discuss these options thoroughly with a healthcare provider to understand the potential benefits and risks. - Lifestyle Recommendations
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Lifestyle recommendations for managing Lewy Body Dementia can help improve quality of life and potentially slow progression of symptoms. These recommendations include:
1. **Regular Exercise:** Engage in physical activities such as walking, swimming, or yoga to improve overall health and maintain muscle strength.
2. **Nutritious Diet:** Consume a balanced diet rich in fruits, vegetables, whole grains, lean proteins, and healthy fats to support brain health.
3. **Mental Stimulation:** Participate in cognitive activities like puzzles, reading, or engaging in hobbies to keep the brain active.
4. **Sleep Hygiene:** Establish a regular sleep routine and create a conducive sleep environment to improve sleep quality, which can help manage symptoms.
5. **Social Interaction:** Maintain social connections through regular interactions with friends and family to help reduce feelings of isolation and depression.
6. **Stress Management:** Practice relaxation techniques such as mindfulness, meditation, or deep breathing exercises to manage stress levels.
7. **Safety Measures:** Make modifications in the living environment to prevent falls and ensure safety, such as removing tripping hazards and installing grab bars.
8. **Medication Management:** Adhere to prescribed medications and consult healthcare providers regularly to monitor and adjust treatments as needed.
9. **Routine Medical Check-ups:** Regular visits to healthcare professionals to monitor the progression of the disease and manage co-existing conditions. - Medication
- Pharmacological management of DLB is complex because of adverse effects of medications and the wide range of symptoms to be treated (cognitive, motor, neuropsychiatric, autonomic, and sleep). Anticholinergic and dopaminergic agents can have adverse effects or result in psychosis in individuals with DLB, and a medication that addresses one feature might worsen another. For example, acetylcholinesterase inhibitors (AChEIs) for cognitive symptoms can lead to complications in dysautonomia features; treatment of movement symptoms with dopamine agonists may worsen neuropsychiatric symptoms; and treatment of hallucinations and psychosis with antipsychotics may worsen other symptoms or lead to a potentially fatal reaction.Extreme caution is required in the use of antipsychotic medication in people with DLB because of their sensitivity to these agents. Severe and life-threatening reactions occur in almost half of people with DLB, and can be fatal after a single dose. Antipsychotics with D2 dopamine receptor-blocking properties are used only with great caution. According to Boot (2013), "electing not to use neuroleptics is often the best course of action". People with Lewy body dementias who take neuroleptics are at risk for neuroleptic malignant syndrome, a life-threatening illness. There is no evidence to support the use of antipsychotics to treat the Lewy body dementias, and they carry the additional risk of stroke when used in the elderly with dementia.Medications (including tricyclic antidepressants and treatments for urinary incontinence) with anticholinergic properties that cross the blood–brain barrier can cause memory loss. The antihistamine medication diphenhydramine (Benadryl), sleep medications like zolpidem, and benzodiazepines may worsen confusion or neuropsychiatric symptoms. Some general anesthetics may cause confusion or delirium upon waking in persons with Lewy body dementias, and may result in permanent decline.
- Repurposable Drugs
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Regarding Lewy Body Dementia, several repurposable drugs have shown potential benefits. These include:
1. **Rivastigmine**: Originally used for Alzheimer's disease, it can help manage cognitive symptoms.
2. **Donepezil**: Another Alzheimer's drug, it can improve cognition and behavior.
3. **Memantine**: Also used for Alzheimer's, it may stabilize or slow the progression of symptoms.
4. **Quetiapine**: An antipsychotic that can manage behavioral and psychiatric symptoms with fewer risks than other antipsychotics.
5. **Carbidopa-Levodopa**: Used for Parkinson’s disease, it can help alleviate movement-related symptoms.
It is crucial to consult a healthcare provider before starting any medication, as they can cause side effects and interact with other treatments. - Metabolites
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Lewy body dementia is associated with several metabolite alterations, which can be detected in related biological studies. Key metabolites often observed include:
1. **Glutamate and Glutamine**: These neurotransmitters are involved in excitatory signaling in the brain and may show imbalances.
2. **Choline-containing compounds**: Changes in these compounds can reflect alterations in cell membrane turnover and integrity.
3. **N-acetylaspartate (NAA)**: Often used as a marker for neuronal health, with reductions typically indicating neuronal loss or dysfunction.
4. **Dopamine**: Reduced levels due to the loss of dopaminergic neurons, which is a hallmark of Lewy body dementia.
5. **Lactate**: Elevated levels can indicate altered brain metabolism and mitochondrial dysfunction.
Monitoring these metabolites may provide insights into the disease progression and effectiveness of therapeutic interventions. - Nutraceuticals
- For Lewy Body Dementia, there are currently no well-established nutraceuticals proven to effectively treat or significantly alter the course of the disease. Some studies suggest that antioxidants, omega-3 fatty acids, and certain vitamins might have potential benefits, but these are not formally recommended treatments. Always consult healthcare professionals before starting any new supplement regimen.
- Peptides
- In the context of Lewy body dementia (LBD), the primary peptide of interest is alpha-synuclein. This protein aggregates to form Lewy bodies, which are abnormal deposits within nerve cells and are a hallmark of the disease. These aggregates disrupt normal cell function, leading to the symptoms associated with Lewy body dementia, such as cognitive decline, visual hallucinations, and motor symptoms similar to Parkinson's disease. The exact mechanisms by which alpha-synuclein contributes to the disease pathology are still being researched.