Lewy body dementia (LBD) is an umbrella term that covers 2 closely related diagnoses, dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).

The term LBD covers both PDD and DLB, it is typically used when describing the spectrum of neurodegenerative disease with LB pathology, but the terms PDD and DLB are more commonly used when citing specific experimental and clinical conditions.

LBDs are characterized by the abnormal accumulation of α-synuclein, a protein found abundantly in neurons. In DLB, deposition of α-synuclein in the neocortex and limbic system leads to cognitive decline and a characteristic timeline of symptom onset.

Cognitive symptoms, including visual hallucinations, typically precede or coincide with motor symptoms. Treatment focuses on symptom management, as no preventative or disease modifying therapies currently exist.

Epidemiology

The precise number of people with LBD remains unclear.

(a) PDD
The point prevalence of PDD is close to 30%, and the incidence rate is increased at 4 to 6 times relative to controls.

The cumulative percentage is very high, with at least 75% of people with PD who survive more than 10 years likely to develop dementia. The mean time from onset of PD to dementia is approximately 10 years.

(b) DLB

DLB is the second most common type of dementia after Alzheimer disease. Prevalence remains uncertain due to small study sizes and diagnostic challenges.

Most estimates suggest that DLB accounts for 3% to 7% of dementia diagnoses. DLB is more prevalent than PDD, making it the most common subtype of LBD. Unlike other dementias, DLB occurs more frequently in men than women. The mean age at onset is between 59 and 78 years.

Very few studies have looked at the incidence rates for DLB with reports suggesting incidence rates of 0.1% in the general population, and 3% for all new dementia cases. A recent review examined 22 studies and reported incidence rates between 0.5 to 1.6 per 1,000 person years, accounting for 3% to 7% of dementia cases.

Genetics

DLB is considered a sporadic disorder. Genetic factors have been identified in 60% of cases.

Duplications or mutations in Synuclein Alpha (SNCA), the gene that encodes α- synuclein, facilitate misfolding and aggregation.

The apolipoprotein E (APOE) allele is also implicated, but its mechanism remains unclear.

Other genes are associated with DLB, but they are less clinically relevant. Current research emphasizes epigenetic mechanisms contributing to the development of DLB.

Epigenetic mechanisms

Epigenetic mechanisms in Lewy body dementia (LBD) include DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), which can alter gene expression and contribute to disease.

These mechanisms are thought to be involved in the interaction between genetic and environmental factors and can lead to the up or downregulation of genes relevant to LBD, such as those for APOE and α-synuclein (SNCA).

Pathophysiology

DLB is defined by the pathological accumulation of misfolded α-synuclein.

The pathophysiology of DLB is primarily characterized by the abnormal accumulation of a misfolded alpha-synuclein, which forms clumps known as Lewy bodies (LBs) and Lewy neurites (LNs) in brain cells.

These protein deposits disrupt nerve cell function, leading to cell death and a decline in cognitive and motor abilities.

Other contributing factors include mitochondrial dysfunction, neuroinflammation, and a reduction in certain brain chemicals like acetylcholine.

Key pathophysiological features are:

1. Alpha-synuclein aggregation
2. Neuronal damage and death
3. Neurochemical imbalances
4. Mitochondrial dysfunction
5. Neuroinflammation
6. Co-pathology (Overlapping pathology from Alzheimer’s disease, including the presence of neurofibrillary tangles, without an amyloid core. This mixed pathology influences the clinical

 

Fig 1: Dementia with Lewy bodies (DLB) pathogenesis and clinical correlation.

Making the Diagnosis

DLB may be misdiagnosed as other neurodegenerative or systemic diseases. The differential diagnosis includes Alzheimer Disease, PDD, vascular dementia, normal pressure hydrocephalus (NPH), delirium, and other parkinsonian disorders.

Alzheimer’s Disease(AD)

AD involves the accumulation of extracellular amyloid-beta plaques and intracellular tau tangles that cause neuronal death.

It is associated with slow onset and gradual progression of memory loss.

Episodic memory loss is most common due to early involvement of the mesial temporal structures.

Behavioral disturbances reflect changes in the frontal region.

Other clinical manifestations include difficulty finding words, impaired facial recognition, and impaired reasoning.

Visual hallucinations and extrapyramidal symptoms, common in DLB, are not typically present in AD.

 

 

Table 1: Neuropsychological deficits in AD and LBD

 

Parkinson’s Disease Dementia(PDD)

PDD shares pathologic features with DLB, including the aggregation of α- synuclein into LBs and LNs.

The key differentiator is timing.

In PDD, cognitive symptoms and visual hallucinations emerge at least 1 year after the onset of motor symptoms such as rigidity, bradykinesia, masked facies, and shuffling gait. In DLB, cognitive decline, visual hallucinations, and motor symptoms occur concurrently or with cognitive symptoms preceding.

There is ongoing debate regarding the validity of the 1-year rule between PDD and DLB researchers. Further confusing the clinical picture, the signs and symptoms of LBD may resemble the more widely recognized dementia syndrome of AD (particularly in the early stages).

Vascular Dementia

Vascular dementia is characterized by cognitive decline associated with cerebral infarcts.

It involves loss of function occurring in a stepwise fashion along with focal neurologic abnormalities such as aphasia, hemiparesis, and spasticity.

Parkinsonian features may also be seen.

Imaging typically demonstrates ischemic changes, and clinical presentation varies based on the brain areas affected.

Risk factors include hypertension, diabetes, hypercholesterolemia, cigarette smoking, and obesity.

Normal Pressure Hydrocephalus

NPH presents with the clinical triad of gait impairment, urinary incontinence, and cognitive dysfunction.

The classic gait disturbance is described as a magnetic gait, because the feet appear to be stuck to the floor during ambulation. This may be confused with a parkinsonian gait.

Imaging shows enlarged ventricles without significant brain atrophy. Lumbar puncture confirms normal cerebrospinal fluid pressure and may provide temporary symptomatic relief.

Delirium

Delirium is a sudden change in mental status characterized by acute confusion, a fluctuating course, inattention, and sometimes hallucinations.

It is common in older adults with cognitive dysfunction or dementia, particularly during hospitalization and in the presence of underlying illness or substance use.

Delirium can be life-threatening and is associated with high rates of morbidity and mortality in this population. In cases of new or acute-onset visual hallucinations in individuals with preexisting dementia, a bedside screening tool such as the Confusion Assessment Method (CAM) can help evaluate delirium. Potential causes of delirium are often multifactorial.

Fig 2: Confusion Assessment Method (CAM) to detect delirium in hospitalized non-intubated patients

Table 2: Other differential diagnosis of DLB (Parkinsonism)

 

Risk Factors for DLB

Nonmodifiable risk factors for DLB include age and family history.

Risk increases substantially in individuals with a first-degree relative who has DLB, including a 2-fold increase if a sibling is affected.

Depression and rapid eye movement sleep behavior disorder (RBD), characterized by acting out dreams through excessive extremity movement and shouting, are recognized risk factors.

SNCA and APOE mutations are established genetic contributors.

Low caffeine intake may increase risk, whereas cigarette smoking has not shown consistent effects.

Clinical Presentations

DLB presents with progressive cognitive decline, often beginning with inattention and executive dysfunction.

A hallmark feature is fluctuating cognition resembling delirium.

Recurrent and well-formed visual hallucinations—often of children or animals—are highly characteristic. The presence of hallucinations can differentiate DLB from other forms of dementia, but the absence of hallucinations should not be used to rule out DLB.

Memory impairment is common, it typically progresses more slowly than in AD. Extrapyramidal motor symptoms such as resting tremor, rigidity, and bradykinesia typically develop later or alongside cognitive decline. Additional features include orthostatic hypotension and urinary incontinence.

RBD is frequently observed and may precede other symptoms by up to 10 years.

Autonomic dysfunction is a common clinical sign in DLB.

Symptomatic orthostasis is probably the most serious manifestation of autonomic dysfunction, but other features include decreased or increased sweating, excessive salivation (sialorrhea), seborrhea, heat intolerance, urinary dysfunction, constipation or obstipation, erectile dysfunction, impotence, and changes in libido.

Constipation may precede any cognitive or motor symptoms by more than a decade. Other constitutional features include anosmia and excessive daytime sleepiness.

Diagnosis

The diagnosis of DLB involves cognitive and movement assessments, polysomnography, imaging, and laboratory testing. Diagnostic criteria are sorted into essential, core, supportive, and indicative features.

Definitive diagnosis can only be made via postmortem biopsy confirming the presence of LBs and LNs.

A DLB diagnosis requires evidence of dementia based on criteria in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision.

Cognitive impairment must affect at least 1 domain and interfere with daily function.

Screening tools such as the Montreal Cognitive Assessment (MOCA) or the Mini-Mental Status Exam are commonly used, with MOCA preferred for early detection.

Visual hallucinations may be evaluated using instruments like the North-East Visual Hallucination Interview.

Table 3: Diagnostic criteria for DLB

 

Movement assessments should be conducted by neurologists or movement disorder specialists. Relevant tools include the Movement Disorder Society Unified Parkinson’s Disease Rating Scale, which evaluates motor components through history and physical exam. Bradykinesia, rigidity, and resting tremor are findings consistent with DLB.

Polysomnography is used to detect RBD by measuring eye movements, muscle activity, and electroencephalogram waveforms during sleep. REM sleep without atonia indicates RBD. The presence of RBD is a core feature of DLB and may present years before cognitive decline.

No specific laboratory studies can confirm a diagnosis of DLB.

Routine blood testing—such as complete blood count, comprehensive metabolic panel, thyroid function, and cobalamin levels—can help exclude potentially reversible causes of dementia.

Biomarkers

Although there are no biomarkers specific for DLB, revisions to diagnostic criteria recognize the move to incorporate biomarkers to increase specificity of clinical diagnoses.

The most common biomarker used in dementia clinical and research evaluations is MRI.

Cortical atrophy is common to many neurodegenerative diseases with the relative preservation of medial temporal lobe structures in DLB may help distinguish it from AD.

Positron emission tomography (PET) may reveal glucose hypometabolism in the medial temporal and occipital lobes, dopamine transporter scans (DAT scan) can identify reduced uptake in the basal ganglia and magnetic resonance imaging can help rule out other disorders.

Imaging can be used to assess peripheral tissues as well. Meta- iodobenzylguanidine (MIBG) cardiac scans may demonstrate decreased uptake, reflecting loss of autonomic neurons. Abnormal MIBG imaging results from the reduction in noradrenergic innervation of the myocardium in LBD, but this may also be seen in other conditions that affect the autonomic nervous system such as diabetes mellitus.

Additional tests may be considered depending on the clinical presentation. Biomarker research is ongoing, with efforts focused on measuring α-synuclein in peripheral and central nervous system tissues.

The fourth consensus for LBD report (2017) advances the previous consensus criteria by incorporating biomarker presence along with redefining the core features to allow the diagnosis of probable DLB.

Abnormal biomarker evidence alone, in the absence of a core clinical feature is not sufficient to diagnosis probable DLB.

Table 4: Features of DLB

Treatment of DLB

No disease-modifying therapies currently exist for DLB.

Treatment involves symptom control and quality of life (QoL), typically via a multidisciplinary approach combining pharmaceuticals (all used off-label), physiotherapy, and psychosocial interventions.

Pharmacologic Therapy

Acetylcholinesterase inhibitors, such as donepezil and rivastigmine, are first- line agents for the cognitive symptoms of DLB.

Memantine, an N-methyl-D-aspartate receptor antagonist, may provide additional benefit.

Dopaminergic medications like levodopa are occasionally used to treat extrapyramidal symptoms and improve movement but may exacerbate psychiatric symptoms.

Zonisamide, an anticonvulsant, showed improvement in motor symptoms without worsening cognitive function in phase 3 trials in Japan.

Atypical antipsychotics may be considered for psychiatric features but should be used with extreme caution, or be avoided, because of the neuroleptic sensitivity seen in DLB and their potential to exacerbate motor symptoms. Melatonin is safe and well tolerated for RBD but may have variable efficacy.

Clonazepam may reduce nocturnal movements associated with RBD but should be used with caution as it can increase risk for falls and worsen cognitive impairment.

Physiotherapy

Physical, occupational, and speech therapy are essential components of supportive care and maintaining QoL in DLB.

Physical therapy focuses on increasing muscle strength and balance to reduce gait disturbances.

Occupational therapy supports greater independence by improving performance in activities of daily living (ADLs).

Targeted speech therapy aims to preserve language function and assess risk for aspiration through swallowing tests. If aspiration risk is identified, modified diets may be recommended to ensure safe oral intake.

Psychosocial Interventions

Psychosocial interventions play a critical role in managing the behavioral and psychological symptoms of DLB, particularly to decrease agitation and risk for injury.

Cognitive behavioral therapy (CBT) and the recognition of visual hallucinations can help alleviate psychiatric symptoms. Music therapy has been shown to decrease agitation.

Reorientation during episodes of cognitive fluctuation can lessen confusion and temporarily enhance cognitive performance but can also paradoxically increase agitation.

A stable and familiar living environment is recommended to minimize disorientation, and a clean, uncluttered space can help reduce fall risk.

Table 5: DLB treatment options

 

Complications

DLB causes progressive decline in language, memory, attention, visuospatial perception, executive function, and social cognition, ultimately leading to loss of functional independence.

As the ability to perform ADLs deteriorates, many individuals require in-home caregiving or admission to skilled nursing facilities.

Mood changes ranging from agitation to depression are common. Worsening visual hallucinations often exacerbate stress, agitation, and confusion.

DLB is also associated with various physical and autonomic complications. Aspiration pneumonia is the most common cause of hospitalization.

Autonomic dysfunction can manifest as urinary incontinence, constipation, and orthostatic hypotension as the disease progresses and autonomic nerve fibers become involved.

Falls tend to increase in frequency as motor symptoms worsen. RBD can result in injury from falling out of bed or hitting nearby objects during sleep.

Prognosis

Research on the prognosis of DLB remains limited.

Overall, prognosis is considered worse when compared with other forms of dementia. DLB is associated with more rapid rates of cognitive decline and greater reduction in life expectancy.

No disease-modifying medications are available, and reversal of LB and LN pathology is not possible.

Symptomatic treatments may offer temporary relief, they do not alter the underlying disease process. As the disease progresses, cognitive decline, motor dysfunction, and visual hallucinations typically worsen. Complications of dementia are the most commonly reported cause of death in individuals with DLB.

Survival times vary widely, ranging from 2 to 20 years after diagnosis, with an average survival time of 6 years.

Summary

DLB is characterized by the abnormal accumulation of α-synuclein into LBs and LNs I subcortical, limbic, and neocortical regions.

Core features include fluctuating cognition, visual hallucinations, RBD, and extrapyramidal motor symptoms. Movement disturbances typically manifest concurrently with or shortly after the onset of cognitive symptoms.

Diagnosis is based mostly on clinical presentation and supported by imaging, although DLB is commonly misdiagnosed as another form of neurodegenerative dementia.

Continued phenotypic characterization of prodromal stages of disease (RBD, autonomic dysfunction, anosmia) may improve our understanding of the earliest clinicopathological changes associated with LBD.

Currently, no disease-modifying therapies exist. As a result, treatment requires a multifactorial approach to reducing symptoms and maintaining quality of life.

Increased awareness of DLB is essential to improving diagnostic accuracy and encouraging further research into pharmaceutical interventions.

References

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Author Information

Thar Thar Oo
M.B; B.S.,MD, MPH,FAAN
Senior Consultant Neurologist