Diagnosis and prevention of dementia with Lewy bodies

Geriatric dementia

With the progress of global aging, Alzheimer's disease has attracted widespread attention
as a disease that seriously endangers the health of the elderly.
At present, there are few books on senile dementia in China, so "Geriatric Dementia" provides a comprehensive and scientific discussion on this field, which has important academic value
。 "Geriatric Dementia" includes two parts, the general article and the sub-article, which mainly elaborates on the definition, classification, epidemiology, etiology and pathophysiology of senile dementia; The main content of the sub-paper includes ten common types of dementia in old age: Alzheimer's disease, vascular dementia, Parkinson's disease dementia, frontotemporal dementia, Lewy body dementia, Huntington's disease dementia, dementia caused by infection and related diseases, dementia caused by substance poisoning, metabolic disorder dementia, and other types of dementia
.
The sub-paper comprehensively expounds
the concepts, epidemiology, pathophysiology, diagnosis, treatment, and prevention of ten common types of dementia in old age.

Chapter Five: Lewy Body Dementia

Section 1 Overview of Lewy Body Dementia

Dementia with Lewy body (DLB) is one of the most common neurodegenerative diseases, its main clinical features are fluctuating cognitive dysfunction, visual hallucinations and Parkinson's disease syndrome, the patient's cognitive impairment often precedes motor symptoms, the main pathological feature is Lewy body (LB), which is widely distributed in the cerebral cortex and brainstem, Pathologic features are neurodegenerative diseases
in which the cerebral cortex and subcortical nuclei diffuse Lewy inclusion bodies.

Frederick Lewy first discovered an intracytoplasmic inclusion body in the substantia nigra cells of the midbrain in patients with primary PD in 1912, and other scholars later confirmed the existence of this inclusion body and named it Lewy body (LB).

In the 60s, pathologists discovered that LB was also present in the neocortex of some dementia patients, and at that time it was considered that such dementia patients were quite rare
.
It was not until the 80s that new histochemical staining techniques became available, which made it easier to detect LB, so more and more patients with dementia were found to be associated
with LB.

In 1961, Okazaki et al.
first described the pathology and clinical manifestations of this type of dementia patients in detail, and proposed the name
DLB 。 Since then, other nouncture names have been used with DLB, such as diffuse Lewy body disease, cortical Lewy body disease, senile dementia of Lewy body type, and Alzheimer's Lewy body variant of Alzheimer’s disease）
。 In 1995, the first International Working Conference on Lewy Inclusion Body Dementia unified the naming of the disease, called Lewy inclusion body dementia, or Lewy body dementia (DLB has not been listed as a separate disease unit in ICD-10 and DSM-V).

Because the clinical manifestations and pathological features are different from other types of dementia, most scholars believe that the disease has constituted an independent disease, DLB accounts for 15%~25% of elderly dementia patients Pathological histological examination shows that the incidence of DLB in senile dementia ranks second only to Alzheimer's disease
.

Section 2

Epidemiology of dementia with Lewy bodies

The incidence and prevalence of dementia increase with ageForeign surveys show that the prevalence of dementia is 1% in people over 60 years old and up to 40% in people over 85 years old in the elderly dementia, statistics from European and American countries show that: AD accounts for about 50%; DLB accounts for 15%~25% of
elderly dementia patients.
The age of onset of DLB is mostly 50 to 80 years old, and the average age of onset is 74.
7 years
.
The proportion of the disease is greater in men than in women, the course of the disease is generally 6 years, and the progression is faster
than AD.

There are few
epidemiological investigations on the prevalence of DLB.
According to non-population-based studies, the prevalence of DLB accounts for 3.
0%~26.
3% of all dementias in people over 65 years of age, similar
to the results of autopsy of 15%~25%.
Based on a small number of demographic surveys, the prevalence of DLB is 0.
1%~2.
0% in the elderly over 65 years old and 5.
0%
in the elderly over 75 years old.
DLB usually has a familial predisposition
.
The prevalence of dementia in people over 60 years old in China is 0.
75%~4.
69%, DLB has also been reported, but no classified incidence statistics have been seen
.

Section 3

Etiology and pathogenesis of dementia with Lewy bodies

The etiology and pathogenesis of DLB are unknown
.
Studies have confirmed that cholinergic and monoaminegic neurotransmitter damage in DLB patients may be related to
cognitive impairment and extrapyramidal dyskinesia.
Genetic studies have found that some DLB patients and familial PD patients have mutations in the α-synuclein gene, and the gene product α-synuclein is both a component of LB and age plaques, which is speculated to be related to the onset of DLB; In addition, the apolipoprotein ε4 gene may also be a risk factor
for DLB.

The pathological hallmark of DLB is Lewy bodies (LB).

LB is mainly composed of abnormal aggregation of insoluble α-synuclein, which causes α-synuclein to become abnormally folded filamentous protein from normal soluble state and may be the central link
of the pathogenesis.

LB is widely distributed in the cerebral cortex and subcortical nucleus of DLB patients, and it is a kind of eosinophilic round body
in the cytoplasm.
It is generally believed that LB is an abnormal aggregation of α-synuclein from soluble to insoluble, and factors affecting the expression and metabolism of α-synuclein may be related to
the pathogenesis of DLB.
In some DLB and familial PDs, there are gene mutations in α-synuclein, resulting in its 5th threonine being replaced by alanine, causing α-synuclein to change from soluble to insoluble and abnormally aggregate; Neurofilaments are mainly subabnormal aggregations of their triplets, which affect the function of tubulin and impair
the function of neurons.
LB under electron microscopy is osmium fondation particles mixed with spiral tube or double helix filament.

LB has been reported to be positive for ubiquitinated protein, while tau protein and β-amyloid are negative, indicating a significant difference from
the typical pathological changes of AD.
There are many diseases with pathological features of LB, among which primary α-synucleinopathy mainly includes DLB, primary PD and multisystem atrophy, and LB
can also be found in the brain of AD patients.

Despite growing awareness of the disease, there is controversy about the relationship between DLB and PD and AD, especially the presence of dementia symptoms in PD during disease progression, and many researchers believe that LB spectrum disease
exists.
LB is found in the brain in more than 40% of AD patients, sometimes referred to as the LBD variant of AD (LBV-AD), indicating an overlap between AD and DLB, making the diagnosis and treatment of the disease difficult
.
This consensus refers to the third DLB consensus written by Mckeith et al.
and the diagnostic criteria for Lewy body cognitive dysfunction (NCDLB) released by DSM-5, combined with the latest research literature, to systematically elaborate
the clinical features, diagnosis and treatment of DLB.

Section 4

Clinical manifestations of dementia with Lewy bodies

Core manifestations: fluctuating cognitive dysfunction, visual hallucinations, extrapyramidal dysfunction
.

Suggestive: abnormal behavior during rapid eye movement during sleep (RBD), sensitivity to neuroleptics, functional imaging
of dopaminergic transporters.

Supportive manifestations: recurrent falls and syncope, transient unexplained loss of consciousness, severe autonomic dysfunction, other forms of hallucinations, delusions, depression, neuroimaging showing relative preservation
of medial temporal lobe structures.

Volatility cognitive impairment:

1.
Severe cognitive decline in the early stage is more common in pathological AD/DLB variants, pathologically accompanied by AD features;

2.
Fluctuating cognitive dysfunction is an early onset and progressing symptom of a severity sufficient to affect daily life and work;

3.
Volatility performance can change greatly within weeks or even within 1 day from minutes to hours, alternating abnormal and normal states, showing dramatic changes;

4.
Patients show cortical and subcortical cognitive impairment, which may have attention, executive ability, and visuospatial dysfunction;

5
.
May preserve memory in the early stages.

Cognitive dysfunction is characterized by poor attention, visuospatial ability, structural ability, and word fluency
.

Visual hallucinations:

Vivid and repeatable; Early stage of the disease can occur - late stage;

Hallucinations caused by adverse anti-PD drug reactions must be identified; Functional brain imaging may show abnormalities in cortical blood flow and function, indicating a possible good response to
cholinesterase inhibitors.

Parkinsonism:

Incidence 75% to 80%; Associated with substantia nigra cell degeneration and reduction of dopaminergic projection fibers; Early onset of severe extrapyramidal symptoms is more common in pathological simplicity (without pathological manifestations of AD); Brady, increased muscle tone, and mask face are the most common, with less tremor, simultaneous onset on both sides, and poor response to dopamine therapy; Extrapyramidal signs occur simultaneously with dementia, or both sequentially within 1 year
.

Abnormal behavior during rapid eye movement sleep (RBD)

Occurs during rapid eye movement sleep, characterized by muscle relaxation and intermittent loss during sleep, manifested as increased physical activity and spasticity, and may have complex and intense limb or trunk movements such as buckles, arm swinging, accompanied by dream memories; Polysomnography shows increased muscle tone under the bucci or limbs during sleep; RBD typically occurs several years before dementia appears and is a common feature
of other α-synaptic common nucleodysplinopathy.

Sensitivity to neuroleptic drugs

Due to the antagonistic blocking effect of neuroleptics on D2 receptors, about 50% of DLB patients will have exacerbated extrapyramidal symptoms, even life-threatening
.

Functional imaging of dopaminergic transporters

Dopamiminergic transporter (DAT) function is reduced in DLB patients and DAT function is normal in AD patients, which can distinguish between the two diseases, but is difficult to distinguish
from PDD.

In recent years, there have been more and more studies on the prodromal phase of AD and
PD.
Some studies suggest that non-amnesic cognitive impairment precedes the appearance of typical DLB symptoms, fluctuating cognitive impairment is relatively rare, and prodromal symptoms
such as REM sleep behavior disorder, visual hallucinations, depression, delirium, Parkinsonism-like manifestations, anosmia, constipation, and orthostatic hypotension 。 As the disease progresses, typical clinical features of DLB gradually appear, the main characteristic symptoms of which include a decline in thinking and reasoning skills; Multiple alternations of confusion and wakefulness within a day to several days; About 50% of patients present with PD-like motor symptoms including trunk arching posture, balance disturbance, and muscle rigidity; visual hallucinations; Delusion; Difficulty processing visual information; abnormal dreams of REM sleep; Sleep disorders; Autonomic dysfunction; Memory impairment less severe than AD, etc
.

The following clinical symptoms help distinguish DLB from AD: fluctuations in cognitive function, with changes in arousal and attention, evidence of fluctuations being excessive daytime sleepiness (with adequate nighttime sleep conditions), or sleep time of more than 2 hours during the day, prolonged staring into the distance, episodic disordered language, visual hallucinations
.
In addition, anterograde amnesia is a prominent sign and symptom of AD that appears early in the disease, whereas DLB anterograde amnesia is not prominent
.
Mckeith et al.
believe that DLB is better than AD in cognitive tests such as naming, short-term or medium-term recall, and rerecognition, while AD is superior to DLB
in terms of language fluency, visual perception and executive function.
Patients with DLB have more impairment of executive function and visuospatial function than AD, such as the stroop test and the digital breadth test
.

Other symptoms that alert clinicians to the diagnosis of DLB (compared with AD) include: visual hallucinations, delusions, unexplained syncope, REM sleep disorder, and psychotropic sensitivities
.

Section 5

Auxiliary examination for dementia with Lewy bodies

1Physical and cognitive examination:

Patients have symptoms and signs similar to PD, but do not meet the diagnostic criteria for PD, have mild gait disorders, but cannot be explained by the patient's old age and osteoarthropathy, resting tremor is less common than PD, and myoclonus occurs before severe dementia
.
Orthostatic hypotension is common in DLB, even when
dementia symptoms are not severe.

DLB usually presents with cognitive impairment
consistent with dementia.
In one study using a simple mental state examination (MMSE) as a cognitive score, DLB:AD:AD+DLB was (15.
6 ±8.
7) points: (10.
7±8.
6) points: (10.
6 ±8.
6) points, DLB cognitive tests were relatively good, and other periods of confusion and silence became characteristic of
DLB.
Memory retrieval is more impaired than memory storage, and naming tests are relatively better
than visuospatial tests (such as clock painting and digital transcription).

2.
Laboratory tests:

Laboratory tests do not provide a basis for diagnosing DLB, but can suggest a risk
of certain dementia types.
Routine dementia tests include biochemistry, blood count, thyroid function, and vitamin B12 level; If necessary, testing
for syphilis, Lyme disease, or AIDS may be done.
CSF is not routinely tested
.
In recent years, studies of cerebrospinal fluid in patients with DLB have found that the cerebrospinal fluid tau of AD patients is higher than DLB, LBV-AD is somewhere in between, and the CSF Aβ levels of DLB, LBV-AD and AD are higher than normal, but there is no difference
between the three.
APOE allele testing can indicate the risk of
AD.

3.
Imaging examination:

(1) MRI: MRI of the head helps to distinguish vascular dementia from DLB, and patients with vascular dementia often have leukoischemic lesions, but DLB does not
.
The medial temporal lobe structure of DLB includes hippocampal atrophy that is lighter than AD, but heavier than normal controls; The Maynert basal nucleus and putamen atrophy of DLB were more pronounced than AD.
DLB has cortical atrophy in the middle and posterior cingulate gyrus, the upper tempo-occipital lobe, and the orbital surface of the prefrontal lobe, while AD is in the parahippocampal gyrus, cingulate gyrus knee, and temporal pole
.

(2) SPECT/PET: SPECT or PET examination in DLB patients can detect decreased occipital blood flow or metabolism, but not in AD patients; SPECT with dopamine transport molecules as ligands can be used to aid in the diagnosis of DLB, and abnormal dopamine transport has a sensitivity of more than 78% and a specificity of more than 90%
for the diagnosis of DLB.
Lim et al.
performed SPECT and PET examinations on 14 patients with clinical diagnosis of DLB and 10 patients with clinical diagnosis of AD, of which SPECT used 123I-beta-CIT as tracer and PET used 18F-fluorodeoxyglucose (FDG) as tracer, and found that the middle and posterior part of the cingulate gyrus was relatively intact, which was called cingulate islandism
.
It is 100% specific
for DLB.
Both CIT-SPECT and FDG-PET can be used to aid in diagnosing DLB, but SPECT is more
accurate.

In patients with DLB clinically diagnosed by PET examination with Pit complex B as a tracer, the amyloid distribution was similar to AD, and amyloid deposition was visible in the frontal, parietal, anterior wedge lobes and posterior cingulate gyrus of DLB, while the amyloid deposition was less in patients with PD and dementia, these studies showed that amyloid deposition may aggravate dementia of DLB, but has little effect on the nature of its disease; If no specific treatment for AD and DLB is available, metabolic imaging is not necessary
to improve diagnostic accuracy.

Figure 1 Coronary T1-weighted image (A) and 123I FP-CIT SPECT IMAGING (B) of AD, DLB and normal control (NC).

As shown, the medial temporal lobe of DLB patients and controls is relatively preserved, while patients with AD are significantly atrophied; Significant reductions in dopamine transporter uptake in putamen and caudate nuclei are seen in patients with DLB

Figure 2 AD, DLB, and normal control (NC) 123I-MIBG imaging
.

Imaging is performed
3 hours after contrast injection.
The region of interest includes the heart (H) and the interstitial tissue above (M).

Calculating the cardiac/interstitial tissue (H/M) ratio, patients with DLV have a significantly lower H/M ratio compared with AD and NC

Figure 3 AD, DLB, and normal control 18F-FDG-PET imaging
.

(A) Metabolic imaging of the right brain region; (B) Standard axis image at the rear buckle back level
.
In AD and normal controls, occipital lobe metabolism is normal, but occipital lobe metabolism is significantly reduced in DLB patients (blue arrow).

In addition, in DLB patients, the posterior cingulate gyrus (yellow arrow) 18F-FDG uptake is normal, while the uptake of the adjacent occipital cortex is reduced, which is called the cingulate gyrus insula

4.
Pathological examination:

The characteristic pathologic of dementia with Lewy bodies is LB, which often coexists
with AD-like pathology.
LB is mainly found in the brainstem, limbic system, and neocortex
.
AD-like pathology is characterized by different degrees of age plaques and neurofibrillary tangles
in different sites.

Highly probable DLB has a neocortical diffuse LB and low or moderate AD-like pathologic findings
, or limbic LB and low-grade AD pathology.

Moderately likely DLB has LB and moderate AD-like pathologic findings predominant to the limbic system, or diffuse LB and high-grade AD-like findings
in the neocortex.

Low-grade likely DLB has brainstem-predominant LB with any degree of AD-like presentation, or limbic system-predominant LB and high-grade AD-like findings
.
See Table 1 for details

Table 1 Evaluation of the possibility of pathological manifestations associated with the typical Lewy body dementia clinical syndrome

5.
Others:

DLB has EEG abnormalities, usually earlier than AD, but is not currently
used as a differential diagnosis.
In some cases, neuropsychological testing may be used to distinguish DLB from AD, or as a baseline
for later evaluation.

Figure 4 Normal REM sleep (A) and typical REM sleep behavior disorder (B).

As shown in the figure, there is no electromyoelectric activity in the sub-chin, leg, and arm leads in figure A, suggesting muscle flaccidation; The same leads in patients with B-chart show increased EMG activity, particularly in the arm leads

Section 6

Dementia with Lewy bodies and diagnostic criteria

DLB has been more than a hundred years since Frederick Lewy first discovered Lewy bodies in the substantia nigra cells of the midbrain in patients with primary Parkinson's disease in 1912, and has been studied by many pathologists around the world for nearly a century, and finally confirmed as a group of dementia syndromes
.
In 1996, McKeith et al.
first proposed the diagnostic criteria for DLB, and in 2005, the International Lewy Body Dementia (DLB) Union issued the first guidelines for the diagnosis and treatment of DLB, which have been widely recognized and applied
.
After 12 years, the DLB Alliance has once again updated the diagnostic criteria for DLB, and a new DLB Alliance consensus report
was published in Neurology magazine in June 2017.
Compared with the 05 criteria, the new diagnostic criteria clearly distinguish between clinical features and biological markers; According to the different clinical characteristics and biological markers of patients, the possibility of diagnosis is divided into "probable" DLB and "probable" DLB
.

Diagnostic criteria for DLB developed by Mickeith et al.
in 2005

Required features (necessary to diagnose possible or likely DLB)

Dementia, progressive cognitive decline, affecting normal social and work abilities
.
Cognitive impairment is most prominent with deficits in attention, executive function, and visuospatial deficits, and significant or persistent memory loss is not necessary in the early stages of the disease, but usually occurs during the progression of
the disease.

Core features (2 core features are required to diagnose most likely DLB, and one core feature is required for possible DLB)

Cue features (at least one core feature plus at least one cue feature can diagnose very likely DLB, lack of core features, only one or more cue features may be considered for diagnosing possible DLB, no core feature can not diagnose very likely DLB)

Supporting features (usually present, but do not increase diagnostic specificity)

Features of DLB are not supported

Diagnosis of DLB is likely to require: 2 core features or at least one core feature plus at least one suggestive feature

Diagnosing possible DLB requires 1 core feature or lack of core features, with only one or more suggestive features

Chronological order in which symptoms occur

Dementia symptoms of DLB usually occur before or at the same time as Parkinson's disease, Parkinson's disease dementia should be based on Parkinson's disease dementia, in clinical practice, the most suitable term should be selected, sometimes a general term such as Lewy body disease can be used, the "1-year principle" is usually used to distinguish DLB and PDD in research, that is, Parkinson's disease Dementia within 1 year is DLB, PDD after one year, and some studies use other time intervals, but this will make it difficult to compare studies, In some clinicopathological studies or clinical trials, 2 clinical subtypes are usually included, called Lewy body disease or α synucleinopathy
.

2017 Diagnostic Criteria for Clinical Diagnosis of Probable and Probable DLB (New Edition)

Required features (necessary to diagnose possible or likely DLB)

Dementia: progressive cognitive decline that affects normal social and work abilities
.
Significant or persistent memory loss is not necessary in the early stages of the disease, but usually occurs during the progression of the disease, and cognitive impairment may be more prominent in the early stages of attention, executive function, and visuospatial deficits.

Core features (the first 3 may present early and persist throughout the course of the disease)

Cue features

Suggestive biomarkers

Supportive biomarkers

Features that do not support DLB:

Diagnosing most likely DLB needs to be met:

A.
≥ 2 core clinical features; with or without evidence of suggestive biomarkers; or

B.
Evidence of suggestive biomarkers that meet only one core feature with ≥ one
.

Biomarker alone does not diagnose likely DLB
.

Diagnosing possible DLB requires the following:

A.
Only one core feature is met, and there is no evidence of suggestive biomarkers; or

B.
Evidence of suggestive biomarkers of ≥1, but no core features
.

Chronological order in which symptoms occur

Dementia symptoms of DLB usually occur before or at the same time as Parkinson's disease, Parkinson's disease dementia should be based on Parkinson's disease dementia, in clinical practice, the most suitable term should be selected, sometimes a general term such as Lewy body disease can be used, the study to distinguish DLB from PDD recommends the "1-year principle", that is, Parkinson's disease within 1 year of dementia is DLB, and PDD
is one year later.

DLB is less likely to be considered if the following criteria are met:

A.
The presence of any other medical or brain disease sufficient to partially or fully explain the patient's clinical symptoms
.
In this case, the possibility of mixed or multiple lesions needs to be considered, even if the diagnosis of DLB cannot be completely ruled out; or

B.
In patients with severe dementia, the core clinical feature is only symptoms of parkinsonism, and it
appears as the first symptom.

Note: DLB refers to dementia that precedes or cooperates
with Parkinsonism.
Parkinson's dementia (PDD) refers to dementia that occurs in people with pre-existing Parkinson's disease
.
In clinical studies where a strict distinction between DLB and PDD is required; The 1-year principle of onset of symptoms in dementia and parkinsonism is still recommended
.

The two editions have the following changes in the diagnostic criteria for DLB:

1.
According to clinical symptoms and signs, it is divided into core features and suggestive features, and the original supporting features are canceled

2.
Added biomarker content, mainly PET/SPECT, intercardiac iodobenzylguanidine scintigraphy, PSG, MRI/CT, electroencephalogram, etc.
, and divided into two types
: suggestive and supportive.

3.
Rapid eye movement sleep behavior disorder has been upgraded from the old cue feature to the core feature; The content of clinical signs or symptoms of the previous supporting features (e.
g.
, repeated falls or syncope, unexplained loss of consciousness, severe autonomic dysfunction, etc.
) was elevated to suggestive features; The imaging content of the older Cue features and supporting features is divided into the Biomarkers section
of the new edition.

The new DLB clinical diagnostic criteria provide a clear distinction
between clinical symptoms/signs and diagnostic biomarkers.

In 2013, DSM-5 published diagnostic criteria for NCDLB

Core features: fluctuating cognitive dysfunction, characterized by changes in attention and alertness; Recurring visual hallucinations of vivid content images; Spontaneous Parkinson's sign, following
cognitive decline.

suggestive features: meet criteria for REM sleep behavior disorder; Abnormal sensitivity to neuroleptics; These impairments cannot be better explained by other conditions, such as cerebrovascular disease, other neurodegenerative diseases, drug effects, or other psychiatric, neurological, or systemic disorders
.

The DSM-5 criteria divide NCDLB into mild, mild cognitive impairment and major, dementia
.
The diagnosis of severe disease is necessary with progressive cognitive dysfunction, and is characterized
by the three core symptoms of fluctuating cognitive dysfunction, PD-like dyskinesia and visual hallucinations.
Cognitive dysfunction in DLB is characterized by complex early changes in attention and executive performance, hallucinations, depression and delusions fluctuate in a deranged pattern, and PD-like dyskinesia symptoms often appear within
a year before or after cognitive impairment.
Parkinson's sign needs to be distinguished from
neuroleptic-induced extrapyramidal symptoms.
REM sleep behavior disorder and abnormal sensitivity to neuroleptics are suggestive features of DLB, and extreme caution
is required when treating psychiatric symptoms with these medications.
NCDLB is supported by frequent recurrent falls and unexplained loss of consciousness such as syncope and brief episodes of loss of consciousness, and autonomic dysfunction such as orthostatic hypotension and urinary incontinence
may be observed.
A mild diagnosis of NCDLB is indicated in patients who develop cognitive or functional impairment at some stage without sufficient core or supportive points to meet criteria
for severe neurocognitive impairment (NCD).
However, for all mild NCDs, there is often insufficient evidence for any single cause, and an unspecified diagnosis is most appropriate
.

The difference between DLB and Parkinson disease dementia (PDD) is internationally controversial, and some experts recommend that these two types be diagnosed
separately as different diseases.
Previous diagnoses have often been made over a one-year period, and it is considered that patients with cognitive impairment are more
likely to diagnose PDD one year after the onset of motor symptoms in Parkinson's disease.
However, some scholars believe that in view of the pathological consistency between DLB and PDD, which are different clinical types of the same type of disease related to α-synuclein, clinical diagnosis can only be defined by the time of movement disorders and cognitive impairment, which should be two subtypes
of one disease.

Differential diagnosis:

In the diagnosis of DLB, according to the different signs and symptoms, it needs to be differentiated from a variety of diseases, common are AD, PDD, corticobasal degeneration, frontotemporal dementia, vascular dementia, hydrocephalus, lacunar syndrome, prion disease, progressive supranuclear palsy, and multisystem atrophy
.
DLB should be clinically mainly differentiated
from AD and PDD.
The differential diagnosis mainly depends on clinical manifestations and pathological features
.
Neurocognitive scale testing is helpful in the differential diagnosis
of AD and DLB.
AD is mainly examined in terms of memory, language, attention and executive function, and the influence of visual spatial function is late
.
DLB, on the other hand, is mainly checked from the aspects of attention and executive functions and visuospatial functions; Memory and language function are uncertain.

The time cut-off point of the '1-year principle' in the diagnosis of DLB and PDD is entirely artificial to distinguish between the two, and if the "1-year principle" is not followed and the clinical
manifestations cannot be accurately distinguished.
Most patients with PDD develop dementia in the middle or late stages of PD
.
Molecular imaging tests such as PET-CT scan are very helpful in the identification of AD, PDD, and DLB, such as 11C-PIB PET-CT labeled amyloid plaque molecular imaging indicates that the load of amyloid plaque in the brain of PDD is significantly lower than that of DLB
.

AD: mainly manifested as progressive cognitive decline, often due to forgetting, fiction to make hallucinatory depiction ambiguous, mental behavior abnormalities, advanced patients may have extrapyramidal symptoms, not easy to distinguish from DLB, DLB cognitive impairment is fluctuating, visual hallucinations are specific and vivid, patients can be visually described and believed; There is significant visual impairment, extrapyramidal manifestations appear early, and CT and MRI show diffuse cortical atrophy
.
AD and LBD behave similarly and are difficult to distinguish
.
In the early or middle stages of the disease, it can be differentiated
by symptoms of cognitive function, psychotic symptoms, and neurological symptoms or signs.
LBD has a very pronounced impairment of executive function and visuospatial function, mild memory impairment, and the fluctuation of cognitive function is very prominent
.
AD patients have prominent memory impairment in the early stage, relatively mild impairment of executive function and visuospatial function, and fluctuation of cognitive function is not obvious
.
AD patients may have visual hallucinations, but they are not as vivid and vivid as the visual hallucinations of LBD patients, and the delusional content is not as rich and systematic
as the delusions of LBD patients.
Patients with mild to moderate AD generally do not have Parkinsonism.

Parkinson's disease dementia (PDD) :P D is called primary Lewy body disease, and about 1/3 of PD is associated with dementia, especially in the advanced stages
of PD.
The presence of Lewy bodies in the substantia nigra and other brainstem nerve nuclei is a typical pathologic feature of
PD.
When the inclusion body of Lewy body was first discovered, some people speculated that PD dementia was caused
by the spread of Lewy bodies in the brainstem to the cerebral cortex.
Later studies did prove that there were Lewy bodies in the cortex of PD patients, and the amount of Lewy bodies was closely related to PD dementia, and the more Lewy bodies in the cortex, the heavier
the dementia.
There are indeed difficulties in the clinical differentiation of LBD from PD dementia, and LBD is very similar
to PD dementia from the clinical manifestations.
The key to differentiation is whether early cognitive impairment is accompanied by PD symptom clusters
.
The differential effect of visual hallucinations and fluctuations in cognitive function is determined
on a case-by-case basis.
PD patients often have psychiatric symptoms such as visual hallucinations and delusions in the process of anti-PD drug treatment, and if hallucinations and delusions are indeed related to drugs, the possibility of LBD is small
.
PD can affect
cognitive function test scores and social life functions due to motor symptoms.
PD symptoms improve after drug treatment, cognitive and social function will also improve, so PD dementia can also show fluctuations in cognitive function, so attention should be paid
to it in the differential diagnosis.
If extrapyramidal symptoms have been more than a year before dementia appears, PD dementia is more
likely.
All in all, there is still much controversy
over whether PD and LBD are one or two diseases.
Some call them spectrum of diseases, meaning that the two diseases may be essentially the same disease, but the lesions affect different brain regions and the extent of their effects
.

Vascular dementia: often has a clear history of stroke and focal signs of the nervous system, the disease is progressively progressive, and the neuroimaging is clear, suggesting infarction or hemorrhagic lesions, which is easy to distinguish
from DLB.
Patients with vascular dementia can have secondary parkinsonism, and their cognitive function is also fluctuating, but vascular dementia often has a relatively clear history of cerebrovascular disease, with relatively characteristic neurological symptoms and signs and abnormal brain imaging examination, so the differential diagnosis is not very difficult
.

Creutzfeldt-Jakob disease (CJD): characterized by dementia and extrapyramidal damage, the disease progresses rapidly, extrapyramidal signs are diverse, myoclonus and seizures may occur, and typical EEG changes are helpful in diagnosis
.

Progressive supranuclear palsy (PSP): PSP is difficult to distinguish from DLB before the appearance of eye movement disorders, PSP dementia is subcortical dementia symptoms without fluctuations, visual hallucinations are rare
.

Section 7

Lewy body dementia treatment

DLB as one of the neurodegenerative diseases, so far there is no way to cure the disease, but some drugs have been clinically proven to control symptoms, improve the quality of life of patients and prolong life, so DLB should be identified and diagnosed early, and comprehensive treatment should be carried out early, so that the course of the disease can be scientifically managed
.
Full management includes effective pharmacological and non-pharmacological treatments, the latter also includes aerobic exercise, scientific dietary and nutritional management, and patient and caregiver education and care
.

(1) Drug treatment

Drug therapy for DLB is complex and a challenge
for many neurologists, psychiatrists, geriatrics, and general hospital physicians.
Often multiple treatment modalities or multiple pharmacological therapeutic targets
are employed.
It generally includes symptomatic treatment
of anti-PD motor symptoms, anti-dementia therapy, anti-psychiatric symptoms and autonomic dysfunction.
There are currently no effective drugs that can cure DLB, so the various drugs we are currently applying are only symptomatic treatment
.

1.
Treatment of anti-PD-like motor symptoms:

A single levodopa preparation is preferred for DLB, and approximately 50% of patients will improve
.
The drug should be started in a small dose, slowly increased to the optimal dose, and then maintained therapy
.
Because these drugs are prone to confusion and psychiatric symptoms, they should be used with caution, preferably without anticholinergic drugs
.

2.
Antipsychotic drug treatment:

DLB visual hallucinations are the most common and are often accompanied by delirium, anxiety, depression, and behavioral abnormalities
.
Mild patients do not require treatment, and cholinesterase inhibitors or atypical antipsychotics
should generally be used when pharmacotherapy is required.
Open Drug Studies have confirmed that cholinesterase inhibitors improve psychiatric symptoms of
DLB.
When atypical antipsychotics need to be used, quetiapine, clozapine and aripiprazole are generally used clinically, because typical antipsychotic drugs have more adverse drug reactions, and most patients have hypersensitivity reactions to such drugs, which may significantly aggravate the patient's psychiatric symptoms, so it is contraindicated
.
It should be noted that long-term large-scale use of atypical antipsychotics also has potential serious adverse effects, such as increased heart and stroke risk and mortality, aggravating cognitive impairment, so clinical caution should be used
.
Small to moderate doses can be used after careful assessment of the benefits and harms, but the shortest duration of treatment should be maintained under close supervision and in consultation with a caregiver or even with the patient himself
.

3.
Anti-dementia drug treatment:

DLB patients have a decreased acetylcholine concentration in the brain, and DLB patients receive cholinesterase inhibitory drugs more effectively than AD patients, and the patient's cognitive fluctuations are reduced, alertness is increased, and memory is improved
.
There is currently no FDA-approved drug for the treatment of patients with DLB, but clinical studies have confirmed the clinical efficacy
of certain cholinesterase inhibitors.
Randomized placebo-controlled studies suggest that rivastigmine has some efficacy
in DLB.
A series of open trials has shown that donepezil is also effective
in the treatment of DLB.
Galantamine has only preliminary results from open trials
.
In the drug treatment of DLB antidementia, if the treatment drug is stopped suddenly, there will be a rebound of neurological and psychiatric symptoms, so it is recommended that patients with DLB who are effective in cholinesterase inhibitor treatment should not easily stop the drug or switch to other cholinesterase inhibitors
.
After treatment, patients will improve
apathy, anxiety, poor attention, hallucinations, delusions, sleep disorders and cognitive impairment to varying degrees.
In some patients, signs similar to PD may be transient during treatment, and once severe motor symptoms occur, discontinuation should be considered
.
To avoid cholinergic-like adverse effects of cholinesterase inhibitors such as nausea, vomiting, loss of appetite, diarrhea, and drowsiness, dosing titration or with food is recommended
.
Cholinesterase inhibitors also increase the risk of orthostatic hypotension, falls, and syncope, and should be noted and prevented
.

Memantine, as an antagonist of glutamate, has been approved by the US FDA for the treatment of patients with moderate to severe AD, but has not been approved for the treatment of PDD and DLB
.
Memantine has been suggested to improve cognitive function and neuropsychiatric symptoms
of DLB.
However, there are relatively few
clinical data on memantine for the treatment of DLB.
The clinical efficacy needs to be further studied and verified
.

4.
Treatment of emotional abnormalities and sleep disorders:

Depressive symptoms of DLB are common, and clinically sound treatment options for this symptom are lacking
.
Currently serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are recommended for the drug treatment of depression, tricyclic antidepressants and drugs with anticholinergic effects should be avoided
.
Patients with sleep disorders such as rapid eye movement-related sleep behavior abnormalities can take clonazepam 0.
25 mg before bedtime, melatonin 3 mg and quetiapine 12.
5 mg, etc.
, should be gradually increased, and the efficacy and related adverse reactions
should be monitored.
Melatonin 3 mg before bedtime has also been reported to be more effective in
combination with clonazepam.
Cholinesterase inhibitors may be helpful in
sleep disorders.
Patients with DLB also often present with apathy, and cholinesterase inhibitors
are generally recommended.

The principles of treatment of LBD are the same as those of other dementias, and the main purpose is to improve cognitive function, relieve psychobehavioral symptoms and improve social living ability
.
However, the clinical manifestations of LBD have their own characteristics, such as psychobehavioral symptoms and extrapyramidal symptoms, which often become the main focus of
treatment.
For example, anti-PD drugs can often induce psychiatric symptoms, and antipsychotic drugs can cause extrapyramidal reactions, so the pros and cons
need to be weighed in the selection of drugs.
For the treatment of PD symptoms, compound levodopa, dopamine receptor agonists and other drugs can be used, but dose adjustment
should be paid attention to.
For the treatment of psychiatric symptoms such as hallucinations and delusions, drugs with relatively small extrapyramidal adverse reactions can be used, and classic antipsychotics can be used perphenazine, sulpiride, etc
.
Novel atypical antipsychotics can be selected with Vistastone, olanzapine, and quinopeptide, which have fewer extrapyramidal reactions and are suitable for the treatment
of psychiatric symptoms of LBD.
The atypical antipsychotic clozapine also rarely produces extrapyramidal adverse effects, but can cause leukopenia or deficiency, and the anticholinergic effect and sedative effect are relatively strong, which can aggravate or induce confusion and falls, so it should be used
with caution.
Even psychiatric symptoms induced or exacerbated by antipsychotics can be effectively controlled with antipsychotic treatment, and antipsychotic treatment does not have to be stopped (sometimes the dose may be reduced).

The improvement of this treatment has significantly improved the treatment effect
.

(2) Non-drug support

1.
Aerobic exercise:

Data show that cognitive stimulation training contributes to memory improvement and quality of life in
patients with mild to moderate dementia.
Physical therapy and aerobic exercise are helpful
in maintaining mobility.
Aerobic exercise can also prevent and delay cognitive decline
.
At the same time, tell families to encourage DLB patients to actively participate in aerobic exercise and pay attention to safety
.

2.
Nutrition management:

DLB patients can eat water normally in the early stage, and there are no special regulations on diet, but advanced patients often have dysphagia and malnutrition, at this time, the patient's diet should be changed, mainly soft food or semi-liquid food, and pay attention to supplementing high protein
.
In patients with severe dysphagia and a high risk of aspiration, gastrostomy may be performed to ensure adequate nutrition
.

3.
Patient and caregiver education:

It is necessary to popularize and educate patients, their spouses, family members and caregivers on DLB diseases, and mobilize social forces to care for DLB patients
.

prognosis

DLB is an irreversible and progressive neurodegenerative disease that progresses at a rate that varies from person to person and is thought to be faster than the course
of AD.
Patients with severe DLB may be malnourished due to dysphagia; Due to long-term bed rest, patients are prone to bedsores; Dysphagia and dyskinesia lead to lung infections and patients eventually die from complications
such as paralysis, malnutrition and infection.

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