Dementia with Lewy bodies.

Dementia with Lewy bodies is a chronic loss of cognitive function characterized by the appearance of intracellular inclusions called Lewy bodies in the cytoplasm of cortical neurons. The disease is characterized by progressive impairment of memory, speech, praxis, and thinking.

Distinctive clinical features of dementia with Lewy bodies include fluctuations in mental status, transient confusional states, hallucinations (usually visual), and increased sensitivity to neuroleptics. Dementia with Lewy bodies is more common in men than in women. Progression of the disease may be more rapid than in Alzheimer's disease.

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Epidemiology

Dementia with Lewy bodies is the third most common type of dementia. The onset of the disease is usually observed after the age of 60.

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Pathogenesis

Pathologically, dementia with Lewy bodies is characterized by the presence of changes characteristic of Parkinson's disease (PD) in combination with or without Alzheimer's-type changes. In dementia with Lewy bodies, Lewy bodies are detected in cortical neurons in combination with senile plaques or without Alzheimer's-type changes. The term "dementia with Lewy bodies" was proposed in 1995 by the International Working Conference on this problem. Previously, the disease was referred to as diffuse Lewy body disease, senile dementia with Lewy bodies, and a variant of Alzheimer's disease with Lewy bodies.

Cortical Lewy bodies, the main pathological feature of dementia with Lewy bodies, are found in 15-25% of patients with dementia. Pathological studies show that patients with dementia with Lewy bodies are often clinically misdiagnosed as having Alzheimer's disease.

Diffuse Lewy Body Disease (DLBD) is characterized by dementia, psychotic disorders, and extrapyramidal (parkinsonism) symptoms. The combination of dementia, characterized by fluctuations (sometimes sharp) in its severity, psychotic disorders with transient visual hallucinations (more than 90% of patients) unprovoked by antiparkinsonian drugs, and parkinsonism, the manifestations of which do not fit into the diagnostic criteria of Parkinson's disease, should serve as a basis for suspecting DLBD. DLBD is more common than it is diagnosed.

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Symptoms dementia with Lewy bodies.

Initial cognitive impairments are similar to those of other types of dementia. However, extrapyramidal symptoms differ from those of Parkinson's disease: in dementia with Lewy bodies, tremor does not appear in the early stages of the disease, axial rigidity and gait disturbances occur initially, and the neurological deficit tends to be symmetrical.

Cognitive fluctuation is a relatively specific symptom of Lewy body dementia.

Periods of the patient being alert, with understandable behavior and orientation may alternate with periods of confusion and unresponsiveness to questions, which usually last for days or weeks, but then give way again to the ability to make contact.

Memory is affected, but its deficit is caused to a greater extent by changes in the level of wakefulness and attention deficits than by the actual impairment of mnestic processes, so memories of recent events are affected less than sequential memory for numbers (the ability to repeat 7 numbers in forward and 5 in reverse order). Excessive sleepiness is common. Visual spatial and visual constructive abilities (tests for construction, drawing a clock, copying figures) are affected more than other cognitive functions. Therefore, dementia with Lewy bodies can be difficult to differentiate from delirium, and all patients exhibiting the above symptoms should be examined for delirium.

Visual hallucinations are common and frequent, unlike the benign hallucinations of Parkinson's disease. Auditory, olfactory, and tactile hallucinations are less common.

In 50-65% of patients, delusions of a complex, bizarre nature occur, which differs from Alzheimer's disease, in which simple persecutory delusions are more common. Vegetative disorders usually develop with the occurrence of unexplained syncopal states. Vegetative disorders can occur simultaneously with the appearance of cognitive deficit or after its occurrence. Increased sensitivity to antipsychotics is typical.

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Diagnostics dementia with Lewy bodies.

The diagnosis is made clinically, but the sensitivity and specificity of diagnosis are low. The diagnosis is considered (taken into account) as probable in the presence of 2-3 signs - attentional fluctuations, visual hallucinations and parkinsonism - and as possible if only one of them is detected. Evidence confirming the diagnosis is repeated falls, syncope and increased sensitivity to antipsychotics. The overlap of symptoms of dementia with Lewy bodies and Parkinson's disease can complicate the diagnosis. If the motor deficit inherent in Parkinson's disease precedes and is more striking than cognitive impairment, the diagnosis of Parkinson's disease is usually made. If early cognitive impairment and behavioral changes predominate, the diagnosis of dementia with Lewy bodies is made.

CT and MRI are unremarkable but are initially useful in identifying other causes of dementia. Fluorine-18-labeled deoxyglucose positron emission tomography and single-photon emission CT (SPECT) with ¹²³ I-FP-CIT (Nw-fluoropropyl-2b-carbomethoxy-3b-[4-iodophenyl]tropane), a fluoroalkyl derivative of cocaine, may be useful in identifying dementia with Lewy bodies but are not routinely used. Definitive diagnosis requires brain autopsy.

Clinical criteria for the diagnosis of diffuse Lewy body disease (DLBD):

• Obligatory sign: progressive decline in cognitive functions in the form of frontal-subcortical dementia
• Additionally, at least 2 of the following 3 features are required for a probable diagnosis of diffuse Lewy body disease and 1 feature for a possible diagnosis of diffuse Lewy body disease:
  • fluctuations in the severity of cognitive impairment
  • transient visual hallucinations
  • motor symptoms of parkinsonism (not associated with taking neuroleptics

Additional diagnostic criteria for diffuse Lewy body disease include: increased sensitivity to neuroleptics, repeated falls, syncopal states, hallucinations of other modalities.

A reliable diagnosis of diffuse Lewy body disease is only possible with a pathomorphological examination.

The diagnosis of diffuse Lewy body disease is considered unlikely in the presence of symptoms of previous stroke, changes in neuroimaging, or the detection of any other brain or physical diseases that can explain the observed clinical picture.

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Differential diagnosis

Features that distinguish dementia with Lewy bodies from Alzheimer's disease and Parkinson's disease:

APOE-64 is a risk factor for dementia with Lewy bodies. However, in terms of the prevalence of the APOE-64 genotype, dementia with Lewy bodies occupies an intermediate position between Parkinson's disease and Alzheimer's disease. This may indicate that dementia with Lewy bodies is a combination of Alzheimer's disease and Parkinson's disease.

In patients with dementia with Lewy bodies (without concomitant Alzheimer's pathomorphological changes), the age of onset of dementia is lower, and the disease more often than in combination with Alzheimer's changes begins with parkinsonism, to which dementia subsequently joins. Patients with dementia with Lewy bodies perform worse on tests of praxis, but cope better with tests of reproduction of memorized material, and also have more pronounced fluctuations in the level of wakefulness than patients with Alzheimer's disease. Visual hallucinations are more often observed in dementia with Lewy bodies than in Alzheimer's disease, although the sensitivity of this sign in the differential diagnosis of dementia with Lewy bodies and Alzheimer's disease is quite low. In dementia with Lewy bodies, lower levels of homovanillic acid are found in the cerebrospinal fluid than in Alzheimer's disease, which probably reflects changes in dopamine metabolism in dementia with Lewy bodies. In dementia with Lewy bodies, as in Parkinson's disease, there is a significant reduction in the number of dopamine-producing neurons in the substantia nigra.

The severity of dementia in Alzheimer's disease and dementia with Lewy bodies correlates with the number of Lewy bodies, decreased choline acetyltransferase activity, and the number of neurofibrillary tangles and neuritic plaques. However, in contrast to Alzheimer's disease, in dementia with Lewy bodies there is no relationship between the severity of dementia and the number of neurofibrillary tangles in the neocortex, or with the level of antisynaptophysin activity, which reflects synaptic density. In dementia with Lewy bodies, resting tremor is less common, the asymmetry of parkinsonian symptoms is less pronounced, but more severe rigidity is observed than in Parkinson's disease.

Treatment dementia with Lewy bodies.

Dementia with Lewy bodies is a progressive disorder with a poor prognosis. Treatment is generally supportive. Rivastigmine 1.5 mg orally as indicated, titrated up to 6 mg as needed, may improve cognitive impairment. Other cholinesterase inhibitors may also be helpful. About half of patients respond to antiparkinsonian medications for extrapyramidal symptoms, but the psychiatric manifestations of the disease worsen. If antiparkinsonian medications are needed, levadopa is preferred.

Traditional antipsychotics, even in very low doses, lead to a sharp worsening of extrapyramidal symptoms, and it is better to refuse them.

Treatment of Parkinsonism

Antiparkinsonian drugs in patients with dementia with Lewy bodies often cause psychotic disorders. If parkinsonism interferes with the patient's life, levodopa drugs can be used to correct it, but on average they are less effective than in Parkinson's disease. In general, the data published to date on the effectiveness of antiparkinsonian drugs in dementia with Lewy bodies are insufficient. Baclofen has also been proposed to reduce rigidity.

Treatment of psychotic disorders

Pharmacotherapy of hallucinations and delusional disorders in patients with dementia with Lewy bodies is complicated by their increased sensitivity to neuroleptics. In dementia with Lewy bodies, treatment with a typical neuroleptic is started at a lower dose and then increased more slowly than in other diseases. Clozapine can be used to treat psychotic disorders, but regular monitoring of clinical blood tests is necessary when taking this drug. Risperidone was useful in one open study but ineffective in another. In one study, olanzapine reduced the severity of psychotic disorders in patients with dementia with Lewy bodies, but often caused confusion and drowsiness, as well as an increase in parkinsonism symptoms. Data on the use of other atypical neuroleptics, in particular quetiapine, as well as remoxipride, zotepine, mianserin, and ondansetron in patients with dementia with Lewy bodies are not yet available in the literature.

Treatment of depression

Depression develops in approximately half of patients with Lewy body dementia. It occurs approximately five times more often in Lewy body dementia than in Alzheimer's disease, but with the same frequency as in Parkinson's disease. Depression significantly aggravates the patient's condition, increases mortality and visits to health services, but, unlike many other manifestations of Lewy body dementia, it is treatable. Treatment of depression in patients with dementia can also improve cognitive functions and reduce apathy.

Pharmacotherapy

The choice of an antidepressant is based primarily on the side effect profile, as there is no evidence of superiority in the efficacy of one drug or another in patients with dementia with Lewy bodies with depression. When choosing an antidepressant, it is important to consider its ability to cause an anticholinergic effect, interact with other drugs, cause drowsiness and autonomic disorders.

Electroconvulsive therapy

There are no clinical trials of the effectiveness of electroconvulsive therapy (ECT) in the treatment of depression in patients with dementia with Lewy bodies. However, it has been shown that ECT can reduce the manifestations of depression and the severity of motor impairment in patients with Parkinson's disease. ECT is mentioned as one of the methods of treating depression in patients with dementia and in the Practice Guidelines for the Treatment of Dementia developed by the American Psychiatric Association. Thus, ECT can be used to treat depression in patients with dementia with Lewy bodies. The placement of electrodes, stimulation parameters, and frequency of procedures should be chosen in such a way as to minimize the possible adverse effect on cognitive functions.

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Cholinergic agents in dementia with Lewy bodies

The level of choline acetyltransferase in the neocortex of patients with dementia with Lewy bodies is lower than in patients with Alzheimer's disease. It is not surprising that cholinesterase inhibitors in dementia with Lewy bodies are, on average, more effective than in Alzheimer's disease. In recent years, a number of double-blind, placebo-controlled clinical trials of cholinesterase inhibitors (rivastigmine, donepezil) have been conducted, which have proven their ability to improve attention and other cognitive functions, as well as reduce the severity of behavioral and psychotic disorders, especially in patients with mild to moderate dementia.

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Promising Directions for Drug Discovery in Lewy Body Dementia

Since the cognitive deficit in dementia with Lewy bodies is apparently associated not only with Lewy bodies, therapeutic intervention should also be aimed at other pathological processes, in particular those leading to the formation of amyloid plaques or neurofibrillary tangles. In connection with the emergence of unified criteria for dementia with Lewy bodies, it becomes possible to conduct clinical trials of those drugs that were developed for the treatment of Alzheimer's disease and Parkinson's disease and are potentially capable of influencing the progression of dementia with Lewy bodies. The development of drugs aimed at correcting neurochemical imbalance, antioxidants, neuroprotective drugs, drugs that inhibit amyloid production, tau protein phosphorylation, neurofibrillary tangle formation, synthesis of APOE-e4 gene products, anti-inflammatory drugs, glutamate receptor agonists is promising.