Lewy Body Dementia: Unpacking a Neuropsychiatric Enigma

CATEGORY 1 CME

Premiere Date: March 20, 2023

Expiration Date: September 20, 2024

This activity offers CE credits for:

1. Physicians (CME)

2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

The goal of this activity is to learn the current criteria, unique diagnostic biomarkers, and differential diagnosis of Lewy body dementia (LBD), as well as how to maintain a high index of suspicion in questionable cases, to ensure an accurate diagnosis.

LEARNING OBJECTIVES

1. Understand the unique psychopathology associated with LBD.

2. Understand the diagnostic issues for LBD.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.

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To better understand Lewy body dementia (LBD), it is essential for clinicians to understand the potentially confusing terminology used in its diagnosis—and understanding the terminology means understanding the biology. Misfolded aggregates of the abundant physiological presynaptic protein α-synuclein in the somatodendritic compartment of neurons and glial cells form the basis of a group of disorders called the synucleinopathies.¹ In the Lewy-type α-synucleinopathies, α-synuclein aggregates in the neurons (Lewy bodies) and neuronal processes (Lewy neurites), but the synucleinopathies also include non-Lewy glial cytoplasmic inclusions, axonal spheroids, and other cytoplasmic neuronal inclusions.¹

In idiopathic Parkinson disease (PD) without dementia, PD with dementia (PDD), and dementia with Lewy bodies (DLB), Lewy bodies involve the postganglionic sympathetic neurons. These 3 diseases, collectively, are called Lewy body disease. However, the term Lewy body dementia is used to indicate only PDD and DLB (Figure 1).²

The term atypical parkinsonian syndrome (APS) refers to several disorders, each of which usually presents with parkinsonism with varying pathology. Among the disorders classified as APS are progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), which are both tauopathies, and the preganglionic non–Lewy-type synucleinopathy multisystem atrophy (MSA).

Finally, mixed pathologies are common in the neurodegenerative dementias. Cooccurring Alzheimer disease (AD) pathology is found in about 10% of patients with PD, 35% of those with PDD, and 70% of those with DLB.³ Cooccurring hippocampal TAR DNA-binding protein 43 (TDP43) pathology is reported in around 40% of autopsy-confirmed cases of Lewy body disease (excluding incidental and brain-stem–only disease).⁴

The “1-year rule” is used to distinguish DLB from PDD. If cognitive symptoms emerge at the same time or at least 1 year before movement problems, the diagnosis is DLB, whereas PDD is diagnosed when cognitive impairment occurs more than 1 year after the onset of parkinsonism. The 2015 Movement Disorders Society (MDS) clinical diagnostic criteria for PD recommended making a diagnosis of PD regardless of the presence or absence of dementia, thereby recognizing that the risk of cognitive impairment in PD is constant over time. The criteria also proposed the qualifier PD (DLB subtype) for patients with DLB who eventually also meet the diagnostic criteria for PD. However, the latest diagnostic criteria for DLB still recommend diagnosing PDD when dementia occurs “in the context of well-established Parkinson disease.”⁵

Three phases in the evolution of the neurodegenerative dementias are now generally accepted:

1. prodromal/preclinical, including subjective cognitive decline,

2. mild cognitive impairment (MCI; objective cognitive impairment without functional decline), and

3. dementia (objective cognitive and functional decline).

Since most of the research in LBD has been done using the older clinical constructs of MCI and dementia, this article uses these terms instead of the newer, but not quite synonymous, constructs of major and mild neurocognitive disorder.⁶ A further discussion of the predementia stages of PD and DLB is outside the scope of this article, except to note that the most common cognitive phenotype of Lewy body disease in the MCI stage is nonamnestic. Unlike amnestic patients who revert to normal cognition, nonamnestic patients who revert to normal cognition do not appear to normalize their risk of progression to dementia.^7,8 These clinicopathologic concepts are presented schematically in the Figure 2.

How Common Is LBD?

In community-dwelling patients with dementia 65 years and older, the point prevalence of DLB is around 10%,⁹ with the highest prevalence in those aged 80 to 89 years.¹⁰ PDD accounts for 3% to 4% of the dementias in the community,¹¹ and almost all patients with PD will develop cognitive impairment if they live long enough.⁸ Some 20% of community-dwelling patients with PD are in the MCI stage at initial diagnosis, and they progress to dementia at an annual rate of around 10%.⁸ LBD is more common in men than in women.

Unpacking the Clinical Features

LBD is best understood as a systemic disease with neuropsychiatric symptoms. A side-by-side comparison of the current diagnostic features of PDD and DLB is presented in Table 1.

Deficits can be present in several cognitive domains. Attention is not only impaired but may also fluctuate during the day and from day to day (fluctuating cognition), and information about deficits can be elicited from patients or caregivers by inquiring about spontaneous changes in attention or consciousness, including staring spells, daytime drowsiness or lethargy, and periods of disorganized speech. Almost all patients with DLB with fluctuating cognition have moderate-to-severe parkinsonism.

Three components of executive function—updating, shifting, and inhibition of dominant responses—have been identified on latent variable analysis,¹² and they may all be impaired in LBD. The reduced mental speed (bradyphrenia) that is typically seen in PD is included under executive functions in the 2007 PDD criteria. Phonemic fluency and the clock draw test are recommended for clinical screening, although neither is a pure test of executive functions.

Visuospatial deficits include impairment in visuospatial orientation, perception, and construction. Studies have found minimal, if any, differences in visuospatial impairment between DLB and PDD on neuropsychological testing.^13,14

Although the deficits in LBD are primarily subcortical, deficits in the cortical domains (memory, language) have also been reported in about one-third of those with PDD and one-quarter of those with DLB living in the community.¹⁵ Unlike in AD dementia, the amnestic disorder in LBD is not of the hippocampal type (ie, the memory deficit usually improves with cueing). The 2007 PDD criteria clearly state this and include memory impairment as an associated clinical feature, while the 2017 DLB criteria only mention that memory impairment is “usually evident with progression.” Language deficits are also described under associated clinical features of PDD—“word-finding difficulties and impaired comprehension of complex sentences may be present”—but they are not included in the diagnostic criteria for either probable PDD or DLB.¹⁶

Behavioral symptoms in both sets of diagnostic criteria include psychotic and mood symptoms. The most common psychotic symptoms in Lewy body disease are hallucinations, along with paranoid and phantom boarder delusions.¹⁷ Hallucinations are significantly more common in DLB (occurring in about 80% of cases) than in PDD (40% to 65%) and PD (14%), and visual hallucinations are about twice as common as auditory hallucinations in DLB and PDD.^5,16,17 Characteristics of visual hallucinations do not differ between DLB and PDD¹⁸; they are typically complex, often involving adults, children, or animals, and may be accompanied by minor parkinsonian hallucinations such as false sense of presence and illusions.⁵ Depression is also common in LBD; subsyndromal (minor) depression is about twice as common as major depression, but the frequencies of major and minor depression are not significantly different across DLB, PDD, and PD.¹⁷

Rapid eye movement (REM)-sleep behavior disorder (RBD) is a REM-sleep parasomnia that presents with dream enactment motor and/or vocal behaviors, accompanied by REM-sleep without atonia (RSWA) on polysomnography (PSG). RBD is male predominant—about 85% of patients who experience it are males—and it can result in injuries to the patient or bed partner. Although RBD is not included in the PDD criteria (see Table 1), it is an early symptom of the syncucleinopathies, including MSA,¹⁹ often preceding the onset of other symptoms by several years or even decades. RBD was elevated from a supportive to a core criterion in the 2017 DLB criteria due to evidence that its inclusion improves the diagnostic sensitivity.

Regarding motor symptoms, the diagnosis of PD (bradykinesia with either rest tremor or rigidity, or both) is essential to diagnosing PDD.²⁰ Although the postural-instability gait difficulty (PIGD) and tremor-dominant subtypes are equally represented in PD, PIGD has been reported in almost 90% of patients with PDD in cross-sectional studies.²¹ Spontaneous parkinsonism (one or more of bradykinesia, rest tremor, or rigidity—a lower threshold than for the diagnosis of PD) is a core clinical feature of DLB, but it is absent in around 15% of patients. Axial symptoms are more common than rest tremor in DLB with parkinsonism, and cross-sectional studies have similarly found an overrepresentation of the PIGD subtype in almost 70% of patients with DLB.²¹

Finally, severe antipsychotic sensitivity in DLB deserves a mention. Two patterns of neuroleptic sensitivity have been reported, each in about 50% of patients.²² Exaggerated extrapyramidal symptoms with onset shortly after receiving neuroleptics can reverse upon reducing the dose, on stopping the treatment, or after treatment with anticholinergics. On the other hand, a severe sensitivity reaction—such as sudden onset of sedation, increased confusion, rigidity, immobility, and neuroleptic malignant syndrome—can often be fatal. Severe neuroleptic sensitivity was downgraded to a supportive clinical feature in 2017 since “reduced prescribing of D2 receptor blocking antipsychotics in DLB limits its diagnostic usefulness.”⁵

Both core diagnostic features—the presence of a preexisting diagnosis of PD, and a dementia syndrome in which the functional decline must not be due to the motor or autonomic symptoms—must be present to diagnose probable or possible PDD.¹⁷ A diagnosis of probable PDD also requires impairment in at least 2 of 4 associated cognitive domains—impairments in attention, executive functions, visuospatial skills, and memory (free recall improved by cueing)—with or without at least 1 associated behavioral symptom such as apathy, depressed or anxious mood, hallucinations, delusions, or excessive daytime sleepiness. A diagnosis of possible PDD additionally requires associated atypical cognitive features such as a fluent aphasia or an amnestic syndrome of the hippocampal type, with or without any associated behavioral symptoms.

Dementia is also an essential feature in the diagnostic criteria for DLB in the fourth consensus report of the DLB Consortium.⁵ Probable DLB is diagnosed in the presence of at least 2 core clinical features regardless of the presence of indicative biomarkers, or 1 core clinical feature with 1 or more indicative biomarkers. Possible DLB is diagnosed in the presence of 1 core clinical feature with no indicative biomarker, or 1 or more indicative biomarkers with no core clinical features. Supportive clinical features and biomarkers help support the diagnosis but lack diagnostic specificity.

Alternative diagnoses must be excluded in all LBD cases. Several neurodegenerative disorders can mimic LBD and are summarized in Table 2.

Interpreting the Diagnostic Biomarkers

Diagnostic biomarkers are not included in the 2007 PDD criteria, but a structural brain scan is recommended to evaluate for probable vascular dementia. As in all dementia cases, MRI is the structural imaging modality of choice. Indicative imaging biomarkers in the 2017 DLB diagnostic criteria include reduced dopamine transporter uptake in the basal ganglia as demonstrated by the ¹²³iodine-fluoropropyl-carbomethoxy-3 β-4-iodophenyltropane (¹²³I-FP-CIT) scan, and myocardial postganglionic sympathetic denervation as demonstrated by ¹²³I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy. These and other imaging biomarkers are summarized in Table 3.

The ¹²³I-FP-CIT scan is a sensitive measure of nigrostriatal degeneration. The scan is normal in healthy individuals and in patients with nondegenerative causes of parkinsonism (eg, vascular parkinsonism, medication-induced tremor, psychogenic tremor, essential tremor), and abnormal in—but does not differentiate between—patients with PD/PDD, DLB, and APS.²³ Approved by the FDA in November 2022 for use in patients with suspected DLB, the scan is best used in memory clinics to differentiate DLB from AD dementia.²⁴ The MIBG myocardial scan effectively differentiates PD/PDD and DLB from APS,²⁵ but it is not yet FDA approved for clinical use in LBD. Relative preservation of the medial temporal lobe structures on structural imaging is a supportive biomarker in the 2017 DLB criteria, and an MRI may also be used in clinical practice to exclude APS, vascular parkinsonism, and idiopathic normal pressure hydrocephalus, as well as to rule out any vascular lesions in the basal ganglia that may confound the interpretation of the ¹²³I-FP-CIT scan.²⁶

Nonimaging diagnostic biomarkers in the 2017 DLB criteria include the presence of RSWA on PSG, which is an indicative biomarker, and posterior predominantly slow-wave electroencephalogram (EEG) activity with periodic fluctuations in the pre-α/θ range on quantitative EEG, which is a supportive biomarker. The term pre-α is used here to indicate its slower frequency (5.6-7.9 Hz) that nevertheless suppresses on eye opening.²⁷

Concluding Remarks

DLB and PDD are frequently encountered by clinicians working with older adults in any setting, and they are challenging to diagnose due to their complex and varied multisystem presentations. Accurate diagnosis requires familiarity with the current criteria, the unique diagnostic biomarkers, and the common mimics, as well as maintaining a high index of suspicion in questionable cases. The recent approval of the ¹²³I-FP-CIT scan for use in patients with suspected DLB will greatly help in making early and accurate diagnoses in complex cases. With the 2015 MDS criteria allowing a diagnosis of PD regardless of the presence or absence of dementia and eschewing the one-year rule, PD/PDD and DLB are now best conceived as 2 ends of a clinical spectrum, with movement disorders being prominent in early PD/PDD and nonmotor symptoms dominating the early clinical presentation in DLB.

Dr Aga is a geriatric psychiatrist and adjunct assistant professor at the Layton Aging and Alzheimer’s Disease Research Center, Department of Neurology, Oregon Health and Science University, Portland, OR.

Acknowledgment The author gratefully acknowledges the contribution of Joseph Quinn, MD, who reviewed early drafts of this article and provided valuable suggestions. Dr Quinn is the Ericksen Endowed Professor for Neurodegeneration Research, Director of the Parkinson’s Center and Movement Disorders Program, and Vice chair for Research, Department of Neurology, School of Medicine, Oregon Health and Science University, Portland, OR.

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