Neurocognitive Disorder with Lewy Bodies

Lewy bodies are abnormal aggregations of protein that develop inside nerve cells, contributing to Parkinson’s disease (PD), the Lewy body dementias (Parkinson’s disease dementia and dementia with Lewy bodies), and some other disorders. Lewy bodies are also seen in cases of multiple system atrophy, particularly the parkinsonian variant (MSA-P).

Lewy bodies can be identified under the microscope during histology tests on brain tissue. Lewy bodies appear as spherical masses that displace other cell components. Lewy bodies may be found in the brainstem (within the substantia nigra) or within the cortex. A classical Lewy body is an eosinophilic cytoplasmic inclusion consisting of a dense core surrounded by a halo of 10-nm-wide radiating fibrils, the primary structural component of which is alpha-synuclein. Cortical Lewy bodies are also composed of alpha-synuclein fibrils, but are less defined and lack halos. In histopathology, cortical Lewy bodies are a distinguishing feature for dementia with Lewy bodies (DLB), but may occasionally be seen in ballooned neurons characteristic of Pick’s disease and corticobasal degeneration, as well as in patients with other tauopathies.

Dementia with Lewy bodies (DLB) is the second most common cause of dementia following Alzheimer’s disease. About 0.4% of those over the age 65 are affected with dementia with Lewy bodies (DLB), and between one and four 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. An estimated 10–15% of diagnosed dementias are Lewy body type, but estimates range as high as 23% for those in clinical studies.

Dementia with Lewy bodies usually affects patients aged older than 50 years. The hallmark of DLB is the presence of Lewy bodies, which are intracytoplasmic inclusion bodies that contain synuclein proteins located in the cortical and subcortical neurons. However, these findings are not specific to DLB and may similarly be present in other neurodegenerative diseases. Although the majority of DLB cases are due to sporadic development, DLB may be familial, suggesting a genetic predisposition. People with the disease have a life expectancy of about eight years after diagnosis.

Clinically, DLB is characterized by the development of a triad of features, namely cognitive, neurological, and psychiatric symptoms. The diagnosis of DLB is difficult, given the absence of distinguishing features on imaging and neuropathology. The diagnosis of the DLB is usually made clinically based on history-taking and findings on physical examination in the absence of metabolic, vascular, and degenerative disorders. Unfortunately, the clinical features of DLB frequently overlap with other neurodegenerative diseases, namely Alzheimer’s disease (AD) and Parkinson’s disease, and some experts consider DLB to be part of the Alzheimer’s/Parkinsonism spectrum. Clinicians should rely exclusively on the presence of core and suggestive clinical features that may distinguish DLB from other neurodegenerative disorders that cause dementia and symptoms of parkinsonism, such as Alzheimer’s disease and Parkinson’s disease with dementia (PDD).

Distinguishing features of DLB include the presence of dementia followed by early Parkinsonism symptoms within less than one year of symptoms onset, vivid and detailed visual hallucinations, depressive symptoms, REM sleep disorders, neuroleptic sensitivity, early onset postural instability and falls, and prominent visuospatial and verbal learning impairment. There is currently no cure for DLB, but pharmacologic and non-pharmacologic interventions can help manage DLB and improve the quality of life.

What are Lewy Bodies?

Lewy bodies are abnormal aggregates of protein that develop inside nerve cells. Lewy bodies are identified under the microscope when histology is performed on brain tissue.

Lewy bodies appear as spherical masses that displace other cell components. There are two morphological types: classical (brain stem) Lewy bodies and cortical Lewy bodies. A classical Lewy body is an eosinophilic cytoplasmic inclusion that consists of a dense core surrounded by a halo of 10-nm wide radiating fibrils, the primary structural component of which is alpha-synucleinL. In contrast, a cortical Lewy body is less well defined and lacks the halo. Nonetheless, it is still made up of alpha-synuclein fibrils.

Figure 1. Figure: A. Lewy bodies (synuclein-positive, eosinophilic, neuronal inclusions) in brain tissue of patient with dementia with Lewy bodies (DLB); B. Immunohistochemical staining of Lewy Neurites; C. Immunhistochemical staining of frontal cortex in DLB demonstrates alpha-Synuclein positive inclusions

Classically, Lewy bodies in DLB are initially present in the amygdala. As the disease advances, these Lewy body cells spread to the limbic cortex and then to the neocortex. These findings may explain the predominance of dementia in patients with early DLB and the consequent development of parkinsonism symptoms. The clinical features of DLB are directly associated with the severity of Lewy-related pathology. In turn, the severity is measured by the pattern of regional involvement of Lewy bodies rather than the number of Lewy bodies.

DSM-5 Diagnostic Criteria for Major or Mild Neurocognitive Disorder with Lewy Bodies

• The criteria are met for major or mild neurocognitive disorder AND
• The disorder has an insidious onset and gradual progression AND
• The disorder meets a combination of core diagnostic features and suggestive diagnostic features for either probable or possible neurocognitive disorder with Lewy bodies.

For probable major or mild neurocognitive disorder with Lewy bodies, the individual has two core features or one suggestive feature with one or more core features.

For possible major or mild neurocognitive disorder with Lewy bodies, the individual has only one core feature or one or more suggestive features.

Core diagnostic features of neurocognitive disorder with Lewy bodies include the following:

1. fluctuating cognition with pronounced variations in attention and alertness
2. recurrent visual hallucinations that are well-formed and detailed
3. spontaneous features of parkinsonism, with onset subsequent to the development of cognitive decline
4. suggestive diagnostic features:
   1. meets criteria for rapid eye movement sleep behavior disorder
   2. severe neuroleptic sensitivity
5. disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder

Dementia with Lewy BodIes and Robin Williams

Figure 2. Robin Williams had been suffering from dementia with Lewy bodies prior to his 2014 suicide.

On August 11, 2014, at his home in Paradise Cay, California, renowned actor Robin Williams committed suicide. An examination of his brain tissue suggested Williams suffered from “diffuse Lewy body dementia.” Describing the disease as “the terrorist inside my husband’s brain,” his widow Susan Schneider Williams said that, “However you look at it—the presence of Lewy bodies took his life,” referring to his previous diagnosis of Parkinson’s. She revealed that in the year before his death Williams had experienced a sudden and prolonged spike in fear and anxiety, depression, and insomnia, which worsened in severity to include memory loss, paranoia, and delusions.

The Lewy Body Dementia Association (LBDA) clarified the distinction between the term used in the autopsy report, “diffuse Lewy body dementia”—which is more commonly called diffuse Lewy body disease and refers to the underlying disease process—and the umbrella term Lewy body dementia—which encompasses both Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). According to LBDA spokesperson Dennis Dickson, “The report confirms he experienced depression, anxiety, and paranoia, which may occur in either Parkinson’s disease or dementia with Lewy bodies. . . . In early PDD, Lewy bodies are generally limited in distribution, but in DLB, the Lewy bodies are spread widely throughout the brain, as was the case with Robin Williams.” Ian G. McKeith, professor, and researcher of Lewy body dementias, commented that Williams’ symptoms and autopsy findings were explained by DLB.

Neurocognitive Disorder Due to Parkinson’s Disease

Defining Parkinson’s Disease

Parkinson’s disease is a degenerative disorder of the central nervous system mainly affecting the motor system. Early in the course of the disease, the most obvious symptoms are movement related, including shaking, rigidity, slowness of movement, and difficulty with walking and gait. Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom. Other symptoms include sensory, sleep, and emotional problems. Parkinson’s disease is more common in older people, with most cases occurring after the age of 50; when it is seen in young adults, it is called early onset Parkinson’s disease.

Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging used to rule out other diseases. Parkinson’s disease typically occurs in people over the age of 60, of whom about 1% are affected. Males are more often affected than females at a ratio of around three males to every one female. When it is seen in people before the age of 50, it is called early onset Parkinson’s disease. In 2015, Parkinson’s disease affected 6.2 million people and resulted in about 117,400 deaths globally. On average following diagnosis, people live between seven and 15 years.

Figure 2. The main pathological characteristics of Parkinson’s disease are cell death in the brain’s basal ganglia and the presence of Lewy bodies in many of the remaining neurons. This loss of neurons is accompanied by the death of astrocytes (star-shaped glial cells) and a significant increase in the number of microglia (another type of glial cell) in the substantia nigra, as shown here.

A physician will diagnose Parkinson’s disease from medical history and a neurological examination. There is no lab test that will clearly identify the disease, but brain scans are sometimes used to rule out disorders that could give rise to similar symptoms.

DSM-5 Diagnostic Criteria

The essential feature of neurocognitive disorder due to Parkinson’s disease is the presence of a dementia that is judged to be the direct pathophysiological consequence of Parkinson’s disease. Dementia has been reported to occur in approximately 20–60% of individuals with Parkinson’s disease and is more likely to be present in older individuals or those with more severe or advanced disease.

The dementia associated with Parkinson’s disease is characterized by cognitive and motoric slowing, executive dysfunction, and impairment in memory retrieval. Declining cognitive performance in individuals with Parkinson’s disease is frequently exacerbated by depression. Findings on physical examination include the characteristic abnormal motor signs of resting tremor, evidence of slowness and poverty of movement (such as micrographia), or muscular rigidity and loss of associated movements.

Diagnostic Criteria

A. The criteria are met for major or mild neurocognitive disorder.
B. The disturbance occurs in the setting of established Parkinson’s disease.
C. There is insidious onset and gradual progression of impairment.
D. The neurocognitive disorder is not attributable to another medical condition and is not better explained by another mental disorder.

Major or mild neurocognitive disorder probably due to Parkinson’s disease should be diagnosed if A and B are both met. Major or mild neurocognitive disorder possibly due to Parkinson’s disease should be diagnosed if  A or B is met:

• There is no evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease or another neurological, mental, or systemic disease or condition likely contributing to cognitive decline).
• The Parkinson’s disease clearly preceded the onset of the neurocognitive disorder.

Differential Diagnosis

• Major or mild neurocognitive disorder (NCD) with Lewy bodies
  • This distinction is based substantially on the timing and sequence of motor and cognitive symptoms. For neurocognitive disorder (NCD) to be attributed to Parkinson’s disease, the motor and other symptoms of Parkinson’s disease must be present well before (by convention, at least one year prior) cognitive decline has reached the level of major neurocognitive disorder (NCD) whereas in major or mild NCD with Lewy bodies, cognitive symptoms begin shortly before, or concurrent with, motor symptoms. For mild NCD, the timing is harder to establish because the diagnosis itself is less clear and the two disorders exist on a continuum. Unless Parkinson’s disease has been established for some time prior to the onset of cognitive decline, or typical features of major or mild NCD with Lewy bodies are present, it is preferable to diagnose unspecified mild NCD.
• Major or mild neurocognitive disorder due to Alzheimer’s disease
  • The motor features are the key to distinguished major or mild NCD due to Parkinson’s disease from major or mild NCD due to Alzheimer’s disease. However, the two disorders can co-occur.

Etiology

Parkinson’s disease in most people is idiopathic (having no specific known cause). However, a small proportion of cases can be attributed to known genetic factors. Other factors have been associated with the risk of developing Parkinson’s disease, but no causal relationships have been proven. A number of environmental factors have been associated with an increased risk of Parkinson’s, including pesticide exposure, head injuries, and exposure to heavy metals.

Those with a family member affected are more likely to get the disease themselves. People exposed to certain pesticides or who have prior head injuries have an increased risk for Parkinson’s disease. In contrast, there is a reduced risk for people who smoke tobacco and drink coffee or tea. The motor symptoms of Parkinson’s disease result from the death of cells in the substantia nigra, a region of the midbrain, leading to a dopamine deficit in the brain. The cause of this cell death is poorly understood, but involves the build-up of proteins into Lewy bodies in neurons.

Treatment

There is no cure for Parkinson’s disease, but medications, surgery, and multidisciplinary management can provide relief from the symptoms. There is some evidence that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality. Regular physical exercise with or without physiotherapy can be beneficial to maintain and improve a patient’s mobility, flexibility, strength, gait speed, and quality of life. However, when an exercise program is performed under the supervision of a physiotherapist, there are more improvements in motor symptoms, mental and emotional functions, daily living activities, and quality of life compared to a self-supervised exercise program at home.