Lewy body dementias: One spectrum or two diseases?

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DOI:

Keywords

a-Synucleinopathies, neurodegenerative disease spectrum, precision neurology

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Correspondence

Ambika Nand Jha
Email: nandjha99@gmail.com

Publication history

Received: 25 Apr 2025
Accepted: 10 June 2025
Published online: 8 July 2025

Funding

None

Ethical approval

Not applicable 

Trial registration number

Not applicable

Copyright

© The Author(s) 2025; all rights reserved. 
Published by Bangabandhu Sheikh Mujib Medical University (currently Bangladesh Medical University).
Key messages
Recognising Lewy body dementias as a singular, heterogeneous spectrum rather than as two distinct diagnoses aligns with current neuropathological and biomarker evidence. Abandoning rigid temporal classifications could enhance diagnostic precision, optimise therapeutic decisions, and facilitate inclusion in targeted clinical trials, paving the way for biologically driven, individualised approaches in neurodegenerative disease management. 
Lewy body dementias, encompassing dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), are the second most common form of neurodegenerative dementia following Alzheimer’s disease. Although both syndromes are unified by the pathological hallmark of α-synuclein deposition, their clinical classification remains bifurcated, defined not by distinct mechanisms but by the order in which cognitive and motor symptoms emerge [1]. This longstanding convention, based on an arbitrary temporal rule, is increasingly challenged by overlapping presentations and shared pathophysiological features. The central question remains: Are DLB and PDD distinct entities or phenotypic variants within a broader, continuous disease spectrum? The current diagnostic framework distinguishes DLB and PDD based on a one-year rule: if cognitive impairment precedes or appears within a year of Parkinsonism, DLB is diagnosed; if dementia occurs later in the course of Parkinson’s disease, PDD is assumed. However, this artificial cutoff has little biological basis and often fails in real-world clinical contexts, where symptom onset may be subtle, fluctuating, or ambiguously reported [2]. As a result, many patients fall into diagnostic grey zones, impacting both prognosis and treatment decisions. Clinically, both forms of LBD share core features: fluctuating cognition, REM sleep behaviour disorder, visual hallucinations, and parkinsonism-supported by converging evidence from neuroimaging, biomarker studies, and therapeutic response. 
 
Structural and functional imaging studies have identified overlapping patterns of cortical and subcortical involvement, particularly in dopaminergic and cholinergic networks. Post-mortem studies consistently demonstrate widespread α-synuclein pathology in both DLB and PDD, often accompanied by Alzheimer-type changes such as β-amyloid plaques and tau tangles [3]. These shared pathologies correlate with cognitive decline, psychiatric symptoms, and disease progression in both conditions.
 
Despite these parallels, the temporal distinction remains entrenched in diagnostic criteria issued by the DLB Consortium and the Movement Disorder Society [4]. While useful for clinical categorisation, this model fails to capture the heterogeneity observed across patients and may hinder research by segregating patients with biologically similar diseases. For instance, patients with early psychiatric symptoms and later motor dysfunction may be mislabeled, resulting in suboptimal treatment strategies and exclusion from relevant clinical trials [4]. Importantly, the therapeutic landscape for LBDs also reflects a spectrum-based reality. Both DLB and PDD respond to cholinesterase inhibitors for cognitive and neuropsychiatric symptoms, while dopaminergic agents address motor features [5]. 

Categories

Number (%)

Sex

 

   Male

36 (60.0)

   Female

24 (40.0)

Age in yearsa

8.8 (4.2)

   Education

 

   Pre-school

20 (33.3)

   Elementary school

24 (40.0)

   Junior high school

16 (26.7)

Cancer diagnoses

 

   Acute lymphoblastic leukemia

33 (55)

   Retinoblastoma

5 (8.3)

   Acute myeloid leukemia

4 (6.7)

   Non-Hodgkins lymphoma

4 (6.7)

   Osteosarcoma

3 (5)

   Hepatoblastoma

2 (3.3)

   Lymphoma

2 (3.3)

   Neuroblastoma

2 (3.3)

   Medulloblastoma

1 (1.7)

   Neurofibroma

1 (1.7)

   Ovarian tumour

1 (1.7)

   Pancreatic cancer

1 (1.7)

   Rhabdomyosarcoma

1 (1.7)

aMean (standard deviation)

Categories

Number (%)

Sex

 

   Male

36 (60.0)

   Female

24 (40.0)

Age in yearsa

8.8 (4.2)

Education

 

   Pre-school

20 (33.3)

   Elementary school

24 (40.0)

   Junior high school

16 (26.7)

Cancer diagnoses

 

Acute lymphoblastic leukemia

33 (55)

Retinoblastoma

5 (8.3)

Acute myeloid leukemia

4 (6.7)

Non-Hodgkins lymphoma

4 (6.7)

Osteosarcoma

3 (5)

Hepatoblastoma

2 (3.3)

Lymphoma

2 (3.3)

Neuroblastoma

2 (3.3)

Medulloblastoma

1 (1.7)

Neurofibroma

1 (1.7)

Ovarian tumour

1 (1.7)

Pancreatic cancer

1 (1.7)

Rhabdomyosarcoma

1 (1.7)

aMean (standard deviation)

Table 1 Conventional versus emerging models in Lewy body dementias

Aspect

Conventional dichotomous model

Emerging continuum model

Disease Classification

Dementia with lewy bodies (DLB): Cognitive decline manifests prior to or within 12 months of motor symptom onset.

Disease is conceptualised as a spectrum with overlapping onset of cognitive, motor, psychiatric, and sleep disturbances. No distinct temporal order governs the presentation of symptoms.

Parkinson’s disease dementia (PDD): Dementia emerges after at least one year of established Parkinsonism.

 

Neuropathology

Predominantly characterised by α-synuclein deposits. DLB often demonstrates more prominent cortical involvement, while PDD predominantly affects subcortical structures.

Extensive cortical and subcortical involvement of α-synuclein pathology in both DLB and PDD. Coexistent Alzheimer-type pathologies (β-amyloid plaques, tau tangles) observed across both entities, suggesting shared neurodegenerative processes.

 

Clinical Features

Cognitive impairment follows motor symptom onset in PDD, whereas DLB exhibits early cognitive symptoms. Both conditions feature Parkinsonism, visual hallucinations, fluctuating cognition, and REM sleep behaviour disorder (RBD).

A broader clinical continuum of cognitive, motor, psychiatric, and sleep disturbances with no rigid sequence, indicating that cognitive and motor symptoms may emerge simultaneously or in varying order. Common pathophysiological markers overlap between both forms of LBD.

 

Diagnostic Thresholds

Clear temporal distinction based on the onset of dementia relative to motor features, specifically the one-year cutoff rule for PDD.

Diagnostic boundaries are fluid, guided by clinical, pathological, and molecular markers rather than an arbitrary time frame. Both phenotypes represent variations within a spectrum.

 

Therapeutic Implications

Cholinesterase inhibitors and dopaminergic therapies are commonly employed, but treatment regimens are often stratified based on the temporal progression of symptoms, without regard for underlying pathophysiology.

A unified therapeutic approach tailored to individual patient profiles using biomarkers. Both cholinesterase inhibitors and dopaminergic agents are employed but with careful consideration of the individual patient's symptomatology and the risk of treatment-related side effects.

 

Clinical Trial Design

Clinical trials often restrict inclusion based on rigid diagnostic criteria, such as the one-year temporal cutoff, potentially excluding individuals with early cognitive or psychiatric symptoms and misclassifying patients.

Clinical trials are designed to accommodate the full spectrum of disease, focusing on biomarker-based phenotyping rather than rigid temporal criteria, allowing for more inclusive patient selection and better representation of disease variability.

Category

Key Factors

Weight

Strengths

Strong management support, skilled workforce, compliance with legal regulations

0.338

Weaknesses

Logistical complexity, inadequate segregation, financial constraints

0.13

Opportunities

Industry collaboration, environmental policies, new technology

0.094

Threats

Limited space, lack of coordination, high investment risk

0.329

Pain level

Number (%)

P

Pre

Post 1

Post 2

Mean (SD)a pain score

4.7 (1.9)

2.7 (1.6)

0.8 (1.1)

<0.001

Pain categories

    

   No pain (0)

-

1 (1.7)

31 (51.7)

<0.001

   Mild pain (1-3)

15 (25.0)

43 (70.0)

27 (45.0)

 

   Moderete pain (4-6)

37 (61.7)

15 (25.0)

2 (3.3)

 

   Severe pain (7-10)

8 (13.3)

2 (3.3)

-

 

aPain scores according to the visual analogue scale ranging from 0 to 10; SD indicates standard deviation

Aspect

Conventional dichotomous model

Emerging continuum model

Disease Classification

Dementia with lewy bodies (DLB): Cognitive decline manifests prior to or within 12 months of motor symptom onset.

Disease is conceptualised as a spectrum with overlapping onset of cognitive, motor, psychiatric, and sleep disturbances. No distinct temporal order governs the presentation of symptoms.

Parkinson’s disease dementia (PDD): Dementia emerges after at least one year of established Parkinsonism.

Neuropathology

Predominantly characterised by α-synuclein deposits. DLB often demonstrates more prominent cortical involvement, while PDD predominantly affects subcortical structures.

Extensive cortical and subcortical involvement of α-synuclein pathology in both DLB and PDD. Coexistent Alzheimer-type pathologies (β-amyloid plaques, tau tangles) observed across both entities, suggesting shared neurodegenerative processes.

Clinical Features

Cognitive impairment follows motor symptom onset in PDD, whereas DLB exhibits early cognitive symptoms. Both conditions feature Parkinsonism, visual hallucinations, fluctuating cognition, and REM sleep behaviour disorder (RBD).

A broader clinical continuum of cognitive, motor, psychiatric, and sleep disturbances with no rigid sequence, indicating that cognitive and motor symptoms may emerge simultaneously or in varying order. Common pathophysiological markers overlap between both forms of LBD.

Diagnostic Thresholds

Clear temporal distinction based on the onset of dementia relative to motor features, specifically the one-year cutoff rule for PDD.

Diagnostic boundaries are fluid, guided by clinical, pathological, and molecular markers rather than an arbitrary time frame. Both phenotypes represent variations within a spectrum.

Therapeutic Implications

Cholinesterase inhibitors and dopaminergic therapies are commonly employed, but treatment regimens are often stratified based on the temporal progression of symptoms, without regard for underlying pathophysiology.

A unified therapeutic approach tailored to individual patient profiles using biomarkers. Both cholinesterase inhibitors and dopaminergic agents are employed but with careful consideration of the individual patient's symptomatology and the risk of treatment-related side effects.

Clinical Trial Design

Clinical trials often restrict inclusion based on rigid diagnostic criteria, such as the one-year temporal cutoff, potentially excluding individuals with early cognitive or psychiatric symptoms and misclassifying patients.

Clinical trials are designed to accommodate the full spectrum of disease, focusing on biomarker-based phenotyping rather than rigid temporal criteria, allowing for more inclusive patient selection and better representation of disease variability.

To better understand the distinction between the two diagnostic approaches and their clinical implications, refer to Table 1, which contrasts the conventional model with the emerging continuum model, emphasising how a unified approach can guide more personalised therapies. However, the risk of exacerbating psychosis with dopaminergic therapy in both groups underscores the need for a nuanced approach. As research moves toward disease-modifying treatments, particularly those targeting α-synuclein aggregation, rigid classifications based solely on symptom chronology could limit therapeutic reach and precision. Increasingly, experts advocate for a unified model of Lewy body disorders that integrates clinical, pathological, and molecular data. Biomarker studies-spanning cerebrospinal fluid analysis, PET imaging, and genetic profiling-are beginning to delineate shared and subtype-specific signatures [6]. A shift toward biologically informed classification could enhance diagnostic accuracy, guide personalised therapy, and improve clinical trial design by accommodating the true complexity of disease presentation. Revisiting the current nosology is not simply a matter of semantics but a call for a paradigm shift in neurodegenerative disease research and care [7]. Recognising LBDs as a spectrum-rather than two arbitrarily separated diseases-aligns classification with emerging biological understanding and paves the way for more tailored, effective interventions.
 
A spectrum-based model of Lewy body dementia can improve diagnostic clarity, personalise therapeutic strategies, and reflect the complex neurobiology of the disease.
Acknowledgements
None
Author contributions
Manuscript drafting and revising it critically: ANJ, VRG, ST. Approval of the final version of the manuscript: VRG, ST, ANJ. Guarantor of accuracy and integrity of the work: VRG, ANJ.
Conflict of interest
We do not have any conflict of interest.
Data availability statement
Not applicable
Supplementary file
None
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