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Dementia is a gradual decline of cognitive functions, including memory, language abilities and problem-solving skills, severe enough to interfere with normal daily functioning. There are many causes of dementia, the most common form being Alzheimer's disease, where memory loss is the most prominent feature. Lewy body dementia contains both Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB). DLB is the second most common cause of dementia in the general population and affects an estimated 1.4 million individuals and their families in the United States.

DLB is named after deposits (cellular inclusions) called Lewy bodies, which are collections of an abnormal protein called alpha-synuclein. Lewy bodies are found throughout the outer layer of the brain (the cerebral cortex) and deep inside the midbrain and brainstem. They can also be found in Alzheimer’s disease, Parkinson’s disease, Down syndrome, and other disorders.

Clinical Features 

DLB consists of a combination of symptoms: dementia, parkinsonism (slowness, stiffness, tremor and problems walking) and visual hallucinations (seeing things that are not real). Patients with DLB may not have significant memory problems in the beginning, but almost always suffer from attention deficits, difficulties organizing and carrying tasks to completion, and problems with their visuospatial abilities. The symptoms usually fluctuate with "good days" and "bad days." The hallucinations in DLB are usually visual, such as anonymous people, family members, small animals or machines. They tend to be in color, very detailed and frequently threatening. Insight is usually retained, especially in the beginning. Many patients with DLB also have repeated falls, faintness and marked sensitivity to certain psychiatric drugs (neuroleptics). Besides hallucinations, other psychiatric symptoms include delusions, depression and apathy. Patients with DLB also tend to act out their dreams and become quite agitated and combative during sleep. This is known as REM sleep behavior disorder (RBD), which may precede the onset of any other symptom of DLB by several years. On examination, besides cognitive impairment and parkinsonian features, many patients with Lewy body dementia have jerk-like movements (myoclonus).

In a study by Gallagher et al (2024), the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years.  Severe dementia may be associated with agitation, disorientation, confusion and hallucinations. These and other psychiatric symptoms often necessitate close supervision by caretakers. DLB and PDD probably represent the two clinical entities on a spectrum of Lewy body disease. The time course of the clinical symptoms differentiates these two conditions. In PDD, dementia develops within the context of an already established diagnosis of Parkinson's disease. In DLB, dementia precedes or coincides with the development of parkinsonian signs for at least one year.

While clinical criteria have been published and revised, accurate diagnosis of DLB remains challenging. One study published in 2024 by Coughlin et al. showed that a substantial proportion of clinically diagnosed participants with DLB had negative alpha-Synuclein Seeding Amplification Assay (αSyn-SAA) results. The study also found that reduced sense of smell (hyposmia) was the strongest clinical predictor of αSyn-SAA positivity. Thus, the researchers concluded that hyposmia and αSyn-SAA may have utility in improving the diagnostic assessment of people with potential DLB.

Cause

The cause of DLB is unknown, but problems with cellular processing of abnormally folded proteins (e.g. alpha-synuclein) in certain brain cells have been suspected to cause the neurodegeneration in brain cortex and in the basal ganglia, the deep portion of the brain involved in control of movement. Although few families with DLB have been described, the disorder is almost always sporadic (not genetic). Analysis of the genetic forms of this disorder allows researchers to work on identifying proteins involved in the disease process. There are some investigators who believed that DLB should be lumped into the PDD group of disorders, rather than separating it into a unique and distinct neurodegenerative disorder. About one-third of Alzheimer's disease patients develop signs of parkinsonism, such as tremor, rigidity, slowed movement, and postural instability. Additionally, patients with PD have a slightly higher risk for Alzheimer's disease than those without PD, but the dementia that is seen in advanced stages of PD appears to be due to progression of PD rather than a co-existent Alzheimer's disease. A gene called APOE4, thought to increase the risk of Alzheimer's dementia, has been found to increase risk of DLB as well.

Treatment

Although DLB patients usually do not respond as well to levodopa as those with typical PD, many do obtain satisfactory improvement with levodopa and benefit from chronic treatment. The treatment of hallucinations, delusions, agitation, and other psychiatric symptoms may be challenging. The traditional antipsychotic drugs (also called typical neuroleptics), such as haloperidol (Haldol), can markedly worsen parkinsonian symptoms, and should not be used.

Pimavanserin (Nuplazid) is a selective serotonin inverse agonist that effectively treats neuropsychiatric symptoms in DLB. By targeting serotonin 5-HT2A receptors without dopaminergic interference, it helps reduce hallucinations and delusions, improving patient quality of life while minimizing motor side effects. Among the other atypical antipsychotic drugs, quetiapine (Seroquel) is usually the first choice to treat neuropsychiatric symptoms such as visual hallucinations without worsening the motor symptoms. However, in difficult cases, a neurologist may consider clozapine (Clozaril), olanzapine (Zyprexa), ziprasidone (Geodon), and aripiprazole (Abilify) as well. However, clozapine can cause loss of infection-fighting white blood cells in one to two percent of cases, a serious side effect that limits the usefulness of this drug. Also, medications used for dementia and behavioral problems associated with Alzheimer's disease, such as donepezil (Aricept), rivastigmine (Exelon), and memantine (Namenda), may be helpful with its neuropsychiatric symptoms too.

In most cases, DLB patients can live at home with careful monitoring and supervision. Some days, they may need more assistance than others but can find reassurance through caregivers help in turning their attention away from hallucinations. Support groups can help by teaching skills in how to communicate with a patient who has dementia. This will help reduce both patient and caregiver frustration.

References

• Armstrong MJ. Advances in dementia with Lewy bodies. Ther Adv Neurol Disord. 2021;14:17562864211057666.
• Coughlin DG, MacLeod KR, Middleton JS, et al. Association of CSF α-Synuclein Seeding Amplification Assay Results With Clinical Features of Possible and Probable Dementia With Lewy Bodies. Neurology. 2024;103(3):e209656. 
• Gallagher J, Gochanour C, Caspell-Garcia C, et al. Parkinson's Progression Markers Initiative. Long-Term Dementia Risk in Parkinson Disease. Neurology. 2024 Sep 10;103(5):e209699
• McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100. 
• Weintraub D. What's in a Name? The Time Has Come to Unify Parkinson's Disease and Dementia with Lewy Bodies. Mov Disord. 2023 Nov;38(11):1977-1981.