Dementia with Lewy bodies (DLB) is a neurodegenerative disease with clinical manifestations of fluctuating cognitive impairment, Parkinson’s syndrome, and psychiatric symptoms highlighted by visual hallucinations. Since it was first proposed by Okazaki et al. in 1961, reports of dementia with Lewy bodies have been increasing. This is due in part to the development of histological techniques, particularly immunohistochemical staining for nucleosome surface proteins and, more recently, all nuclein staining techniques, which have made the staining of the cerebral cortex more clearly visible than before. In the past literature, various terms have been used to describe DLB, including cortical Lewy body disease, senile dementia of Lewy body type, and Lewy body variant of Alzheimer’s disease Alzheimer’s disease, nowadays the unified name is Lewy body dementia.
DLB used to be considered a rare type of dementia. It was only in the late 1980s that the development of anti-ubiquitin staining techniques led to the realization that this type of dementia was not uncommon. This led to the first internationally accepted diagnostic consensus in 1996, and the criteria were revised in 1999. Overall, these diagnostic criteria have a high specificity (79-100%, mean 92%) and a low sensitivity (0-83%, mean 49%) for the identification of DLB. The most recent international diagnostic criteria are the consensus reached by McKeith et al. at an international meeting in 2005 (see Table 1). The criteria continue the clinical and pathological diagnostic criteria of ’96 and ’99, with substantial additions to the supporting evidence, and also incorporate relevant advances in recent years in clinical and basic research in the field of the disease, with the aim of improving the sensitivity of identifying DLB.
Pathological manifestations and pathogenesis
Lewy bodies are spherical, eosinophilic vesicles in the cytoplasm of neurons, mainly composed of α-synuclein, ubiquitin, complement proteins, microfilaments, microtubules, etc. They are located in the brainstem, limbic system and neocortex. etc. It was found that the site of LB involvement was more relevant to disease severity than the absolute LB count. In addition to Lewy vesicles, Lewy neurites (LN), an axonal change, can also be found in DLB. Both LB and LN can be detected by α-synuclein immunohistochemistry and graded semi-quantitatively depending on the severity of the damage (see Figure 1). In addition, neuronal loss, amyloid deposition plaques, and brain atrophy are also present in DLB to varying degrees.
There are three main theories regarding the role played by Lewy vesicles in the pathogenesis of DLB: 1) toxic effects of LB on neurons leading to cell death and cortical atrophy; 2) disruption of normal synaptic transmission function, leading to cortical loss of contact; 3) compensatory overexcitation of neuronal activity and long-term increase in glucose metabolism, eventually leading to malfunction.
Clinical manifestations
The core symptoms of DLB are mainly: fluctuating cognitive functions, recurrent episodes of visual hallucinations with vivid images, and spontaneous Parkinson’s syndrome. Other manifestations with suggestive value are: behavioral disturbances during fast-acting eye phase sleep, high sensitivity to nerve blocking agents, and reduced uptake of striatal dopamine transporters as shown by functional neuroimaging.
1. Cognitive fluctuations
The most significant feature of cognitive impairment in DLB is its fluctuating nature. The patient’s cognitive function fluctuates between normal and abnormal, and fluctuations in arousal status and attention cause the patient to be sometimes fuzzy and sometimes awake. The objective evaluation of symptom fluctuations is a major challenge in practice. The Clinician Assessment of Fluctuation scale for senior clinicians and the One Day Fluctuation scale for junior physicians have been widely used. “The Clinician Assessment of Fluctuation scale for senior clinicians, the One Day Fluctuation Assessment scale for junior physicians, and the Mayo Fluctuations Composite Scale, which is completed by caregivers. Inter-rater reliability of existing assessment instruments for fluctuating symptoms is still reported to be low, so the adoption of a uniform assessment tool and standardized training for clinicians is the future trend.
Table 1 DLB Clinical Diagnostic Consensus Criteria 2005 Revision
1. Required symptoms (necessary for the diagnosis of probable or likely DLB)
Progressive cognitive impairment to the extent that it affects the patient’s normal social and occupational abilities.
Significant or persistent memory loss, which may not be present in the early stages, but often becomes more pronounced as the disease progresses.
Impairment of attention, executive function, and visuospatial ability is particularly significant.
2. Core symptoms (a diagnosis of probable DLB is made when two of the following characteristics are met, and a diagnosis of probable DLB is made when one of the following characteristics is met)
Cognitive fluctuations, especially in the degree of attention and arousal.
Recurrent, vivid and specific visual hallucinations.
Spontaneous Parkinson’s syndrome manifestations.
3. suggestive evidence (on the basis of having one or more core symptoms, having one or more suggestive symptoms can be diagnosed as probable DLB; in the absence of core symptoms, one or more suggestive symptoms can be diagnosed as probable DLB. those with only suggestive symptoms but no core symptoms cannot be diagnosed as probable DLB)
Abnormal behavior during fast-acting eye phase (REM) sleep.
High sensitivity to nerve blockers.
SPECT/PET imaging suggests reduced dopamine transporter uptake in the basal ganglia region.
4. Supporting evidence (more common manifestations, but not yet proven to be diagnostically specific)
Recurrent falls and syncope.
Transient, unexplained loss of consciousness.
Severe autonomic dysfunction, such as upright hypotension, urinary incontinence, etc.
Other hallucinations.
Systemic delusions.
Depression.
CT/MRI shows relatively preserved medial temporal lobe structures.
SPECT/PET shows overall decreased perfusion and occipital lobe hypometabolism.
MIBG myocardial imaging is abnormal (hypo-uptake).
EEG shows significant slowing of EEG activity with transient temporal lobe spike wave emission.
5. Possible exclusion of DLB
Focal neurological signs or imaging suggestive of cerebrovascular disease.
The presence of other physical or brain disorders can explain all or part of the clinical manifestations.
Dementia has reached a severe level and Parkinson’s syndrome party first appears.
6. Order of appearance of symptoms
If a patient has Parkinson’s syndrome, DLB should be diagnosed only if dementia precedes or is concurrent with Parkinson’s syndrome, and when dementia develops after a definite diagnosis of Parkinson’s disease, the diagnosis should be Parkinson’s disease dementia (PDD). In practice, clinically appropriate terms such as “Lewy’s microsomal disease” should be used. When conducting studies to define DLB and PDD, we still recommend a one-year interval between the onset of dementia and Parkinson’s symptoms. The use of other time interval criteria may affect the comparability between studies. Instead, it may be considered as a clinical phenotype of Lewy’s microsomal disease or alpha co-optosis in clinicopathological studies or clinical trials.
2. Visual hallucinations
Recurrent, image-specific visual hallucinations are one of the most important evidences for the diagnosis of DLB and are mostly present in the early stages of the disease. The Neuropsychiatric Inventory (NPI) is currently the most commonly used assessment tool, not only for disease screening, but also for evaluating the frequency and severity of such symptoms. However, the NPI is based on information provided by caregivers, who often do not detect visual hallucinations until they are quite severe, and therefore often underestimate the actual condition. In 2006, McKeith et al. used the IP-VHI (Institute of Psychiatry Visual Hallucination Interview) as an evaluation tool to analyze the frequency, duration, and content of self-reported visual hallucinations. content. It was found that visual hallucinations in DLB and PDD patients usually occurred daily, lasted several minutes each time, and were often unpleasant, mostly in the form of animals or people. It was also found that patients with DLB who experienced visual hallucinations had more prominent visual perceptual impairment compared to patients without visual hallucinations. In addition, the appearance of visual hallucinations was associated with Lewy body density in the anterior and inferior temporal lobes as well as in the amygdala. It has also been suggested that this class of symptoms is closely associated with reduced activity of cortical cholinergic pathways and is therefore more likely to benefit from cholinergic treatment.
Other symptoms that accompany visual hallucinations include emotional indifference, sleep disturbance and anxiety, which often cause great distress to patients’ lives and deserve attention and treatment.
3.Extrapyramidal syndrome
Extrapyramidal syndrome (EPS) is one of the three core symptoms of DLB, and its severity is comparable to that of Parkinson’s disease patients of the same age with or without dementia. Postural instability, gait disturbances, and masked faces are often more pronounced in the midline, and resting tremor is less common. As in Parkinson’s disease, patients with DLB can be evaluated for extrapyramidal symptoms with UPDRS and H&Y grading. However, these patients usually do not respond as well to L-dopa treatment as patients with Parkinson’s disease alone. Analyzing the reasons, this may be related to their endogenous striatal degeneration. It is also suggested that some of the Parkinson’s symptoms in DLB patients may not be of dopa origin.
4. Behavioral abnormalities during sleep
In 2006, Boddy et al. applied the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) and found that, compared with AD, DLB patients had worse sleep quality, mainly manifested by REM
The main manifestation is REM sleep behavior abnormalities (RBD), which often exist years before the onset of dementia and Parkinson’s syndrome. Patients often experience vivid and frightening dreams with murmuring and strenuous movements. They are more common in men than in women and are often improved by the use of clonazepam. The patient is usually unable to recall them after waking, and questioning of co-sleepers is more important. Since patients with Parkinson’s disease and multiple system atrophy also often have RBD, it is thought that this may be a common manifestation of co-nucleopathies.
5. High sensitivity to nerve blocking agents
Ballard et al. reported in 1998 that about 33% of DLB patients showed hypersensitivity to nerve blocking agents, mainly manifested by sudden exacerbation of Parkinson’s syndrome, altered state of consciousness, malignant hyperthermia, etc., which has a very high rate of disability and death. Therefore, nerve blocking agents, especially D2 receptor blockers, should be avoided in this group of patients. Still, nearly half of the patients with DLB treated with classical or non-classical antipsychotics do not experience the above-mentioned hypersensitivity reactions. It should be noted that tolerance to antipsychotic treatment does not exclude the diagnosis of DLB, but hypersensitivity to such treatment is highly suggestive of DLB.
6. Dopamine transporter imaging
The development of functional imaging of the dopamine transporter (DAT) has provided a new means of visualizing the nigrostriatal dopamine system. Currently, a variety of DAT-specific ligands have been used in research and clinical applications, such as FP-CIT, β-CIT, IPT, TRODAT, etc. DAT imaging is abnormal in Parkinson’s disease, multisystem atrophy, and progressive supranuclear palsy. Similarly, dopamine transporter uptake in the nigrostriatal system is reduced in patients with DLB. Colloby et al. also found that the degree of diminished dopaminergic system activity showed a good correlation with clinical cognitive and motor deficits. In AD patients, DAT imaging was normal. Therefore, this test can be used for the differential diagnosis of DLB and AD.
In addition, there are many other clinical manifestations closely related to DLB (see Table 1), which will not be discussed in detail in this paper due to the limitation of space.
Ancillary tests
To date, there are no genetic or biochemical markers that can be used as a basis for the diagnosis of DLB. In addition to the DAT imaging mentioned above, other imaging examinations such as MRI temporal lobe volume measurement, SPECT/PET local cerebral blood flow and metabolic examinations are also reliable adjuncts, and the relative preservation of the hippocampal and middle temporal lobe structures on MRI, shell nucleus atrophy, SPECT/PET superior perfusion and non-atrophic occipital lobe with hypometabolism are all suggestive for the diagnosis of DLB. . In addition, 123I-MIBG myocardial imaging has a high sensitivity and specificity for the differentiation of AD and DLB, but this result needs to be validated by a larger sample study.
Differential diagnosis
The specificity and sensitivity of the clinical diagnosis of DLB is not yet high, and there are many differential diagnostic issues, the most important of which are the differentiation from Parkinson’s disease dementia and AD: 1.
1, Parkinson’s disease dementia (PDD)
PDD and DLB have many overlaps in both clinical and pathological manifestations. Repeated episodes of visual hallucinations are more common in both diseases. Many patients with Parkinson’s disease may experience cognitive impairment in the late stages of the disease, but dementia usually does not manifest until 10 years or more after motor symptoms. However, apart from differences in the order of symptom onset, age of onset, and slight differences in response to L-dopa preparations, patients with DLB and PDD are similar in many areas of cognitive impairment, neuropsychological manifestations, sleep disturbances, autonomic impairment, parkinsonian symptoms, nerve blocker hypersensitivity, and efficacy to cholinesterase inhibitors. Therefore, it has been pointed out that it is not scientific to separate the two, and that DLB and PDD may be different manifestations in the broad Lewy body disease spectrum. From the perspective of clinical practice, the differential diagnosis of the two may be of some value; however, from the perspective of exploring the underlying mechanism of the disease, it may be necessary to think in terms of “monism”.
2. Alzheimer’s disease (AD)
In 2006, McKeith et al. found that, at comparable cognitive levels, DLB patients had more severe functional impairment than AD patients in terms of confrontation naming, short- and medium-term recall and recognition. In 2006, McKeith et al. found that DLB patients had more severe functional impairment and greater motor and neuropsychiatric impairment than AD patients at comparable cognitive levels. Also, patients with this type of dementia were less able to take care of themselves. The previously mentioned 123I-MIBG myocardial imaging may provide some help in the identification. It is worth mentioning that comprehensive assessment tools such as MMSE cannot be used to differentiate DLB from other types of dementia, and some patients with a diagnosis of DLB may even have a normal MMSE score.
Treatment
The treatment of DLB mainly includes the correct early diagnosis, target symptoms and the determination of the ideal regression evaluation index. Current studies on the treatment of DLB, especially large, randomized, double-blind, controlled clinical trials, are quite limited, so it is not possible to propose treatment norms for this disease from the perspective of evidence-based medicine, and the existing treatment opinions are mainly based on the consensus of national expert workshops.
The treatment of DLB consists of two main aspects: non-pharmacological means and pharmacological means. Non-pharmacological interventions such as increased socialization and environmental reinforcement may have beneficial effects on cognitive and psychiatric symptoms, but there is a lack of objective indicators to evaluate them scientifically. Pharmacological treatment may vary according to the target symptoms.
1. Parkinson’s syndrome
Molly et al. 2005 found in a clinical trial that patients with DLB tolerated levodopa well, but only one-third of them were more sensitive to this treatment than PDD (77%) and PD (57%). Younger patients with DLB may be more likely to benefit from dopaminergic treatment, and Molly et al. found that the application of levodopa to treat Parkinson’s symptoms in patients with DLB had less impact on cognitive function but may exacerbate cognitive fluctuations. Overall, treatment of motor symptoms in patients with DLB should start with small doses of L-dopa preparations and increase the dose cautiously and slowly. Anticholinergic drugs should also be avoided.
2. Neuropsychiatric symptoms
Treatment of visual hallucinations and concomitant psychiatric symptoms such as delusions and anxiety can be performed with cholinesterase inhibitors and atypical antipsychotics. To date, one large, two small placebo-controlled clinical trials and nearly 20 open studies have demonstrated the efficacy of cholinesterase inhibitors on cognitive and psychiatric symptoms in patients with DLB and improved their overall condition. They were well tolerated and did not exacerbate patients’ extrapyramidal symptoms. For those patients who do not respond well to cholinesterase inhibitor therapy, a trial of atypical antipsychotics may be considered with caution. However, the clinician must inform the family of the patient’s risk of hypersensitivity reactions. Classical antipsychotics should be avoided. For manifestations such as depression and sleep disturbances, SSRIs and clonidine may be chosen accordingly.
3. Cognitive impairment
As mentioned earlier, cognitive impairment in patients with DLB can also be treated with cholinesterase inhibitors. The latter also has a certain improvement effect on the overall condition and daily living ability of patients. Cognitive impairment in DLB patients has been reported to be more effective with cholinesterase inhibitors than with AD, but long-term follow-up studies are lacking.
With the advancement of pathological staining techniques and the popularization of autopsy work-up, it is increasingly recognized that Lewy’s microsomal dementia is not uncommon and is the second most common type of dementia after AD and VaD. However, in China, many physicians still do not understand the disease, and the phenomenon of underdiagnosis and under-treatment is still common. In addition, although basic and clinical research on DLB has made great progress in recent years, the diagnosis and treatment of the disease still remain at the level of expert consensus. In-depth exploration of new diagnostic techniques, extensive randomized double-blind controlled studies, long-term follow-up to understand the long-term prognosis of patients, improvement of scientific evidence-based medical system, and establishment of scientific diagnosis and treatment standards for clinical practice are still issues that need to be addressed in future work.