Dementia with Lewy bodies
Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior, cognition, movement, and regulation of automatic bodily functions. Memory loss is not always an early symptom. The disease worsens over time and is usually diagnosed when cognitive impairment interferes with normal daily functioning. Together with Parkinson's disease dementia, DLB is one of the two Lewy body dementias. It is a common form of dementia, but the prevalence is not known accurately and many diagnoses are missed. The disease was first described on autopsy by Kenji Kosaka in 1976, and he named the condition several years later.
"DLB" redirects here. For other uses, see DLB (disambiguation).Dementia with Lewy bodies
Diffuse Lewy body disease, dementia due to Lewy body disease
Dementia, abnormal behavior during REM sleep, fluctuations in alertness, visual hallucinations, parkinsonism[1]
Long term[4]
Unknown[4]
Based on symptoms and biomarkers[1]
Variable; average survival 4 years from diagnosis[8]
About 0.4% of persons older than 65[9]
REM sleep behavior disorder (RBD)—in which people lose the muscle paralysis (atonia) that normally occurs during REM sleep and act out their dreams—is a core feature. RBD may appear years or decades before other symptoms. Other core features are visual hallucinations, marked fluctuations in attention or alertness, and parkinsonism (slowness of movement, trouble walking, or rigidity). A presumptive diagnosis can be made if several disease features or biomarkers are present; the diagnostic workup may include blood tests, neuropsychological tests, imaging, and sleep studies. A definitive diagnosis usually requires an autopsy.
Most people with DLB do not have affected family members, although occasionally DLB runs in a family. The exact cause is unknown but involves formation of abnormal clumps of protein in neurons throughout the brain. Manifesting as Lewy bodies (discovered in 1912 by Frederic Lewy) and Lewy neurites, these clumps affect both the central and the autonomic nervous systems. Heart function and every level of gastrointestinal function—from chewing to defecation—can be affected, constipation being one of the most common symptoms. Low blood pressure upon standing can also occur. DLB commonly causes psychiatric symptoms, such as altered behavior, depression, or apathy.
DLB typically begins after the age of fifty,[2] and people with the disease have an average life expectancy, with wide variability, of about four years after diagnosis.[8] There is no cure or medication to stop the disease from progressing, and people in the latter stages of DLB may be unable to care for themselves. Treatments aim to relieve some of the symptoms and reduce the burden on caregivers. Medicines such as donepezil and rivastigmine can temporarily improve cognition and overall functioning, and melatonin can be used for sleep-related symptoms. Antipsychotics are usually avoided, even for hallucinations, because severe reactions occur in almost half of people with DLB,[10] and their use can result in death. Management of the many different symptoms is challenging, as it involves multiple specialties and education of caregivers.
Classification and terminology[edit]
Dementia with Lewy bodies (DLB) is a type of dementia, a group of diseases involving progressive neurodegeneration of the central nervous system.[11] It is one of the two Lewy body dementias, along with Parkinson's disease dementia.[12]
Dementia with Lewy bodies can be classified in other ways. The atypical parkinsonian syndromes include DLB, along with other conditions.[13] Also, DLB is a synucleinopathy, meaning that it is characterized by abnormal deposits of alpha-synuclein protein in the brain. The synucleinopathies include Parkinson's disease, multiple system atrophy, and other rarer conditions.[14]
The vocabulary of diseases associated with Lewy pathology causes confusion.[15] Lewy body dementia (the umbrella term that encompasses the clinical diagnoses of dementia with Lewy bodies and Parkinson's disease dementia) differs from Lewy body disease (the term used to describe pathological findings of Lewy bodies on autopsy).[15] Because individuals with Alzheimer's disease (AD) are often found on autopsy to also have Lewy bodies, DLB has been characterized as an Alzheimer disease-related dementia; the term Lewy body variant of Alzheimer disease is no longer used because the predominant pathology for these individuals is related to Alzheimer's.[15] Even the term Lewy body disease may not describe the true nature of this group of diseases; a unique genetic architecture may predispose individuals to specific diseases with Lewy bodies, and naming controversies continue.[16]
Prognosis[edit]
As of 2021, no cure is known for DLB.[2][4][157] The prognosis for DLB has not been well studied; early studies had methodological limitations, such as small sample size and selection bias.[200] 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.[117][201] Depression, apathy, and visual hallucinations contribute to the reduced quality of life.[202] Decline may be more rapid when the APOE gene is present, or when AD—or its biomarkers—is also present.[203] The severity of orthostatic hypotension also predicts a worse prognosis.[204] Visuospatial deficits early in the course of DLB were thought to be a predictor of rapid decline,[205] but more recent studies did not find an association.[30]
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.[206] Compared to AD, which is better studied, memory is thought to be retained longer, while verbal fluency may be lost faster,[203] but the most common tools used to assess cognition may miss the most common cognitive deficits in DLB, and better studies are needed.[207]
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.[200][208] An increased rate of hospitalization compared to AD is most commonly related to hallucinations and confusion, followed by falls and infection.[209]
Life expectancy is difficult to predict, and limited study data are available.[188] Survival may be defined from the point of disease onset, or from the point of diagnosis.[210] There is wide variability in survival times, as DLB may be rapidly or slowly progressing.[8] A 2019 meta-analysis found an average survival time after diagnosis of 4.1 years[8]—indicating survival in DLB 1.6 years less than after a diagnosis of Alzheimer's.[211] 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.[210] 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;[8] some people with Lewy body dementias live for 20 years.[2] Shorter life expectancy is more likely when visual hallucinations, abnormal gait, and variable cognition are present early on.[188]
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.[212] 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.[213]
In the late phase of the disease, people may be unable to care for themselves.[19] Falls—caused by many factors including parkinsonism, dysautonomia, and frailness—increase morbidity and mortality.[56] Failure to thrive[8] and aspiration pneumonia, a complication of dysphagia (difficulty swallowing) that results from dysautonomia, commonly cause death among people with the Lewy body dementias.[80] Cardiovascular disease and sepsis are also common causes of death.[163]
Epidemiology[edit]
The Lewy body dementias are as a group the second most common form of neurodegenerative dementia after AD as of 2021.[15] DLB itself is one of the three most common types of dementia, along with AD and vascular dementia.[2][214][d]
The diagnostic criteria for DLB before 2017 were highly specific, but not very sensitive,[216] so that more than half of cases were missed historically.[187] Dementia with Lewy bodies was under-recognized as of 2021,[117] and there is little data on its epidemiology.[151] The incidence and prevalence of DLB are not known accurately, but estimates are increasing with better recognition of the condition since 2017.[217]
About 0.4% of those over the age of 65 are affected with DLB,[9] and between 1 and 4 per 1,000 people develop the condition each year.[218][219] Symptoms usually appear between the ages of 50 and 80[9] (median 76[3]), and it is not uncommon for it to be diagnosed before the age of 65.[151]
DLB is thought to be slightly more common in men than women,[3] but this finding has been challenged and is inconsistent across studies.[220] 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.[220] Studies in Japan, France and Britain show a more equal prevalence between men and women than in the US.[220]
An estimated 10 to 15% of diagnosed dementias are Lewy body type, but estimates range as high as 23%[151] for those in clinical studies.[163] 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.[151] Neither of the studies assessed systematically for RBD, so DLB may have been underdiagnosed in both studies.[151] 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.[221]
History[edit]
Frederic Lewy (1885–1950) was the first to discover the abnormal protein deposits in the early 1900s.[222][223] In 1912, studying Parkinson's disease (paralysis agitans),[224] he described findings of these inclusion bodies in the vagus nerve, the nucleus basalis of Meynert and other brain regions.[163][225] He published a book, The Study on Muscle Tone and Movement. Including Systematic Investigations on the Clinic, Physiology, Pathology, and Pathogenesis of Paralysis agitans, in 1923 and except for one brief paper a year later, never mentioned his findings again.[226]
In 1961, Okazaki et al. published an account of diffuse Lewy-type inclusions associated with dementia in two autopsied cases.[222][227] Dementia with Lewy bodies was fully described in an autopsied case by Japanese psychiatrist and neuropathologist Kenji Kosaka in 1976.[228][229] Kosaka first proposed the term Lewy body disease four years later, based on 20 autopsied cases.[40][227] DLB was thought to be rare until it became easier to diagnose in the 1980s after the discovery of alpha-synuclein immunostaining that highlighted Lewy bodies in post mortem brains.[222] Kosaka et al. described thirty-four more cases in 1984, which were mentioned along with four UK cases by Gibb et al. in 1987 in the journal Brain, bringing attention to the Japanese work in the Western world.[230] A year later, Burkhardt et al. published the first general description of diffuse Lewy body disease.[231]
In the 1990s, with Japanese, UK, and US researchers finding that DLB was a common dementia, there were still no available diagnostic guidelines, with each group using different terminology.[232] The different groups of researchers began to realize that a collaborative approach was needed if research was to advance.[233] The DLB Consortium was established, and, in 1996, the term dementia with Lewy bodies was agreed upon,[89] and the first criteria for diagnosing DLB were elaborated.[40]
Two 1997 discoveries highlighted the importance of Lewy body inclusions in neurodegenerative processes: a mutation in the SNCA gene that encodes the alpha-synuclein protein was found in kindreds with Parkinson's disease, and Lewy bodies and neurites were found to be immunoreactive for alpha-synuclein.[234] Thus, alpha-synuclein aggregation was established as the primary building block of the synucleinopathies.[234]
Between 1995 and 2005, the DLB Consortium issued three consensus reports on DLB.[235] DLB was included in the fourth text revision of the DSM (DSM-IV-TR, published in 2000) under "Dementia due to other general medical conditions". In the 2010s, the possibility of a genetic basis for LBD began to emerge.[92] The Fourth Consensus Report was issued in 2017, giving increased diagnostic weighting to RBD and 123I-MIBG myocardial scintigraphy.[236]
Research directions[edit]
The identification of prodromal biomarkers for DLB will enable treatments to begin sooner,[243] improve the ability to select subjects and measure efficacy in clinical trials,[244] and help families and clinicians plan for early interventions and awareness of potential adverse effects from the use of antipsychotics.[245] Criteria were established in 2020 to help researchers better recognize DLB in the pre-dementia phase.[21][246] Three syndromes of prodromal DLB have been proposed: 1) mild cognitive impairment with Lewy bodies (MCI-LB); 2) delirium-onset DLB; and 3) psychiatric-onset DLB.[21] The three early syndromes may overlap.[247] As of 2020, the DLB Diagnostic Study Group's position is that criteria for MCI-LB can be recommended, but that it remains difficult to distinguish delirium-onset and psychiatric-onset DLB without better biomarkers.[247] Nonetheless, severe late-onset psychiatric disorders can be an indication to consider Lewy body dementia,[248] and unexplained delirium raises the possibility of prodromal DLB.[130]
The diagnosis of DLB is made using the DLB Consortium criteria, but a 2017 study of skin samples from 18 people with DLB found that all of them had deposits of phosphorylated alpha-synuclein, while none of the controls did,[249] suggesting that skin samples offer diagnostic potential.[250] Other potential biomarkers under investigation are quantitative electroencephalography, imaging examination of brain structures, and measures of synucleinopathy in CSF.[251] While commercial skin biopsy tests for DLB are available in the US, and the FDA has given a 'breakthrough device' authorization for CSF testing, these tests are not widely available and their role in clinical practice has not been established[252][253] as of 2022.[137][254][255] Other tests to detect alpha-synuclein with blood tests are under study as of 2021.[253]
Cognitive training, deep brain stimulation and transcranial direct-current stimulation have been studied more in Parkinson's and Alzheimer's disease than they have in dementia with Lewy bodies, and all are potential therapies for DLB.[243] Four clinical trials for treating parkinsonian symptoms in DLB have been completed as of 2021, but more studies are needed to assess risk vs. benefits, adverse effects, and longer-term therapeutic protocols.[174]
Strategies for future interventions involve modifying the course of the disease using immunotherapy, gene therapy, and stem cell therapy, and reducing amyloid beta and alpha-synuclein accumulation. Therapies under study as of 2019 aim to reduce brain levels of alpha-synuclein (with the pharmaceuticals ambroxol, NPT200-11, and E2027), or to use immunotherapy to reduce widespread neuroinflammation resulting from alpha-synuclein deposits.[243][256]