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Dementia With Lewy Bodies

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Description: Dementia with Lewy bodies is a type of progressive dementia characterized by the presence of abnormal protein deposits called Lewy bodies in the brain, leading to cognitive decline, visual hallucinations, and motor symptoms resembling Parkinson's disease.
Type: Dementia with Lewy bodies is a neurodegenerative disorder. It generally does not follow a clear pattern of genetic transmission, though some genetic factors may increase the risk. Most cases are sporadic, meaning they occur in individuals without a family history.
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: 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: The onset of dementia with Lewy bodies (DLB) typically occurs in individuals who are aged 50 and older, with symptoms often beginning in their mid-60s to 70s. The progression of the disease can vary, but early symptoms may include fluctuating cognitive impairments, visual hallucinations, and motor symptoms similar to Parkinson's disease.
Prevalence: The prevalence of dementia with Lewy bodies (DLB) is estimated to range from 0.1% to 5% in the general elderly population. It accounts for approximately 4% to 8% of all dementia cases, making it the second most common type of neurodegenerative dementia after Alzheimer's disease.
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: Dementia with Lewy bodies (DLB) is generally considered intractable, as there is currently no cure. Treatment focuses on managing symptoms and improving quality of life.
Disease Severity: Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder, meaning its severity worsens over time. In the early stages, individuals may experience mild cognitive impairment, visual hallucinations, and motor symptoms similar to Parkinson's disease. As the disease progresses, cognitive decline becomes more pronounced, often leading to significant memory issues, pronounced visual and auditory hallucinations, severe motor problems, and fluctuations in alertness and attention. In the advanced stages, individuals may require full-time care. The rate of progression and severity can vary among individuals.
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: Dementia with Lewy bodies is not typically associated with a specific "carrier status" because it is generally not inherited directly in the way some genetic conditions are. It results from the accumulation of abnormal protein deposits called Lewy bodies in the brain. However, there may be a genetic predisposition that contributes to the risk of developing the disease.
Mechanism: Dementia with Lewy bodies (DLB) is a neurodegenerative disorder characterized by the presence of abnormal protein aggregates called Lewy bodies and Lewy neurites in the brain. These inclusions predominantly contain alpha-synuclein protein. The molecular mechanisms underlying DLB involve several key processes:

1. **Alpha-synuclein Aggregation**: Misfolded and aggregated alpha-synuclein is a hallmark of DLB. Aggregated alpha-synuclein forms Lewy bodies and Lewy neurites, which disrupt cellular function.

2. **Mitochondrial Dysfunction**: Mitochondrial impairment is observed in DLB, leading to reduced energy production and increased oxidative stress. This can exacerbate neuronal damage.

3. **Autophagy and Lysosomal Dysfunction**: The cellular mechanisms responsible for disposing of misfolded proteins, such as autophagy and lysosomal degradation, are often compromised in DLB, leading to the accumulation of alpha-synuclein.

4. **Neuroinflammation**: Activated glial cells and increased levels of pro-inflammatory cytokines contribute to chronic neuroinflammation, which can further damage neurons.

5. **Synaptic Dysfunction**: Alpha-synuclein aggregates disrupt synaptic function, affecting neurotransmitter release and synaptic plasticity, which are crucial for cognition.

These molecular disruptions cumulatively lead to the progressive neuronal loss and cognitive decline observed in DLB.
Treatment: For dementia with Lewy bodies, treatment typically focuses on managing symptoms since there is no cure. This can include:

1. **Medications**:
- **Cholinesterase inhibitors** (such as donepezil or rivastigmine) to help with cognitive symptoms.
- **Antipsychotic medications** may be used with caution, as patients with Lewy body dementia are often very sensitive to these drugs.
- **Medications for movement symptoms** like those used in Parkinson’s disease (e.g., levodopa), though they can sometimes worsen other symptoms.
- **Antidepressants** may be prescribed if depression is a symptom.

2. **Non-Pharmacological Interventions**:
- **Cognitive Behavioral Therapy (CBT)**
- **Physical therapy** and **exercise programs** to help maintain mobility and physical function.
- **Speech therapy** for speech and swallowing difficulties.
- **Occupational therapy** to assist with daily living activities.

3. **Safety and Supportive Measures**:
- Creating a safe living environment to prevent falls and injuries.
- Providing support for caregivers, such as respite care and support groups.

Managing dementia with Lewy bodies often requires a comprehensive and tailored approach involving healthcare providers, caregivers, and sometimes medical specialists.
Compassionate Use Treatment: Compassionate use treatment and off-label or experimental treatments for Dementia with Lewy Bodies (DLB) may include the following:

1. **Cholinesterase Inhibitors** (off-label):
- Donepezil and rivastigmine, typically used for Alzheimer's disease, can be prescribed off-label to help manage cognitive symptoms and possibly improve behavior and function in DLB patients.

2. **Memantine** (off-label):
- Though primarily used for moderate to severe Alzheimer's disease, memantine may be considered off-label to help with cognitive symptoms of DLB.

3. **Antipsychotic Medications** (with caution):
- Extremely cautious use of quetiapine or clozapine may be considered for severe neuropsychiatric symptoms. However, these medications have a significant risk of worsening motor symptoms and increasing mortality in DLB patients.

4. **Levodopa** (off-label):
- While mainly used in Parkinson's disease, levodopa may help alleviate some motor symptoms associated with DLB, though it should be used carefully due to potential exacerbation of psychiatric symptoms.

5. **Experimental Treatments**:
- Clinical trials are ongoing for various therapies targeting the alpha-synuclein protein aggregates characteristic of DLB.
- Potential treatments include immunotherapy approaches, small-molecule inhibitors, and other novel compounds designed to modify disease progression.

Patients and caregivers should consult with healthcare professionals to understand the potential benefits, risks, and appropriateness of these treatments for individual cases.
Lifestyle Recommendations: For managing Dementia with Lewy Bodies (DLB), consider the following lifestyle recommendations:

1. **Healthy Diet**: A balanced diet rich in fruits, vegetables, whole grains, lean proteins, and healthy fats can support overall brain health.

2. **Regular Exercise**: Physical activity, such as walking, swimming, or yoga, can improve cardiovascular health and may help maintain cognitive function.

3. **Mental Stimulation**: Engaging in activities that challenge the brain, such as puzzles, reading, or learning new skills, can be beneficial.

4. **Social Interaction**: Maintaining social connections with friends and family can help reduce feelings of isolation and provide emotional support.

5. **Sleep Hygiene**: Ensuring good sleep habits by maintaining a regular sleep schedule and creating a restful environment can help alleviate sleep disturbances, which are common in DLB.

6. **Medication Management**: Regularly consult with healthcare providers to manage medications effectively, as some drugs can exacerbate symptoms of DLB.

7. **Routine and Structure**: Establishing a daily routine and using tools like calendars or reminders can help with memory and daily functioning.

8. **Safety Measures**: Implementing home safety modifications, such as removing trip hazards and installing grab bars, can help prevent falls and injuries.

9. **Stress Management**: Techniques such as meditation, deep breathing exercises, or gentle activities like tai chi can help manage stress and anxiety.

10. **Support Services**: Consider joining support groups or seeking services from organizations that specialize in dementia care for additional resources and support.

Note that individual needs can vary, so it is important to tailor these recommendations to the specific circumstances of the person with DLB.
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: There are several drugs that have been explored for potential repurposing in the treatment of dementia with Lewy bodies (DLB). These include:

1. **Cholinesterase Inhibitors:** Originally developed for Alzheimer's disease, donepezil and rivastigmine are sometimes used to manage cognitive symptoms in DLB.
2. **Memantine:** Though primarily used for Alzheimer's, memantine, an NMDA receptor antagonist, can be considered for cognitive symptoms in DLB.
3. **Antipsychotics:** Low doses of quetiapine are occasionally used, albeit cautiously, to manage neuropsychiatric symptoms, given the heightened sensitivity in DLB patients.
4. **Parkinson's Medications:** Levodopa and other dopaminergic agents, typically used for Parkinson’s disease, may help with motor symptoms in DLB, but they need to be used carefully due to the risk of exacerbating psychiatric symptoms.

Always consult with a healthcare professional for personalized medical advice.
Metabolites: Dementia with Lewy bodies (DLB) is associated with several metabolic changes in the brain. Some pertinent metabolites include:

1. **Dopamine**: Reduced levels due to degeneration of dopaminergic neurons.
2. **Acetylcholine**: Reduced levels because of cholinergic deficits.
3. **Glucose**: Altered glucose metabolism, typically reduced uptake in the brain.
4. **Lactate**: Increased levels may indicate cellular stress and altered energy metabolism.
5. **Phosphocreatine and ATP**: Reduced levels suggest mitochondrial dysfunction and impaired energy metabolism.

These metabolic changes contribute to the clinical and pathological features of DLB.
Nutraceuticals: Nutraceuticals for dementia with Lewy bodies (DLB) may include dietary supplements like omega-3 fatty acids, antioxidants, and vitamins such as vitamin E and B vitamins. These are thought to support brain health and potentially slow cognitive decline. However, their efficacy is still under investigation, and patients should consult healthcare providers before starting any new supplement regimen.
Peptides: In the context of dementia with Lewy bodies (DLB), a key peptide of interest is alpha-synuclein. This protein aggregates abnormally in the brains of individuals with DLB, forming Lewy bodies. These aggregates disrupt normal cellular function and contribute to neurodegeneration seen in the disease. Research into peptides aims to understand and potentially target these aggregates for therapeutic purposes.