Redefining Parkinson’s Disease and Dementia with Lewy Bodies
Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are closely related diseases with overlapping symptoms. In DLB, dementia occurs before movement (or motor) problems; in PD, motor impairments appear first, and dementia may follow. Currently, diagnosis entirely relies on symptoms, their progression and their sequence. As a result, the terms used to diagnose patients vary.
The neuronal α-synuclein disease
Given recent progress, the term ‘neuronal α-synuclein disease’ is proposed to describe both PD and DLB. These diseases share a common feature: the presence of abnormal α-synuclein protein in the brain. When this protein changes shape, it can clump together to form small bundles called fibrils. These fibrils are thought to contribute to the gradual breakdown of neurons that produce dopamine, a chemical messenger in the brain.
As these neurons are lost, patients may experience movement difficulties such as shaking, stiffness, and slowness. They may also encounter cognitive decline, which includes problems with memory, thinking, and decision-making. Additionally, rapid eye movement sleep behaviour disorder may develop as the disease progresses.
The biological definition
Recent advances in detecting abnormal neuronal α-synuclein from the fluid surrounding the brain and spinal cord (cerebrospinal fluid) have enabled the use of this biomarker to diagnose living patients. The diagnosis of neuronal α-synuclein disease is based on the following four criteria:
1. Genetic status of the patient, especially regarding the SNCA gene that codes for the α-synuclein protein, as a variant for this gene has been associated with an abnormal form of the protein
2. Presence of the abnormal neuronal α-synuclein biomarker
3. Deficit in dopamine transporter, which is an indirect biomarker of the loss of dopaminergic neurons
4. Evaluation of clinical symptoms.
Symptoms are key to determining the stage of the disease, especially in advanced forms. These symptoms encompass motor manifestations (such as shaking, stiffness, and slowness) and nonmotor signs (loss of smell, constipation, low blood pressure, irregular heart rate, cognitive problems, depression, and anxiety).
Most patients start at Stage 1, as fully penetrant SNCA variants defined as Stage 0 (or SNCA variants associated with neuronal α-synuclein disease in 100% of cases), are very rare. Stages 1A and 1B are separated based on the hypothesis that the presence of abnormal neural α-synuclein precedes the loss of dopaminergic neurons in the brain. Stages 2A and 2B are defined by the absence or presence of deficit in dopamine transporters. Finally, Stages 3 to 6 describe the increased discomfort of patients in their daily life (Table 1).
Table 1. The different stages of the neuronal α-synuclein disease
Abbreviations: G+, presence of the SNCA variant causing the abnormal form of the α-synuclein; S-, absence of abnormal α-synuclein in patient’s cerebrospinal fluid; S+, presence of abnormal α-synuclein in patient’s cerebrospinal fluid; D-, absence of deficit in dopamine transporter; D+, presence of deficit in dopamine transporter indicating loss of dopaminergic neurons.
Not so fast
The designation of PD and DLB as neuronal α-synuclein diseases, as well as the biological definition, are the result of a global discussion involving international neuroscience associations, clinical experts, industry sponsors, non-profit organisations, regulatory authorities, and representatives of the patient community. Nevertheless, this classification is currently restricted for research purposes only, as its application in clinical settings would be premature and inappropriate.
Why does it matter?
Defining the neuronal α-synuclein disease biologically is a crucial step that can accelerate the development of treatments for all stages of the disease. This definition allows diagnosis of asymptomatic patients through a simple biomarker analysis. It may also highlight that the disease does not always progress linearly from Stage 1 to 6. Furthermore, the proposed definition highlights the areas where improvements are needed. For example, new scales to measure patient discomfort and difficulties in daily life should be developed. This new definition will also expand our current knowledge of other genetic risk variants associated with neuronal α-synuclein disease.
Take home messages
1. PD and DLB share symptoms but differ in onset. DLB starts with dementia, while PD begins with motor impairments.
2. The term “neuronal α-synuclein disease” encompasses both PD and DLB, emphasising their common feature of the presence of abnormal α-synuclein protein in the brain.
3. Detecting abnormal α-synuclein in cerebrospinal fluid opens new diagnostic possibilities, allowing earlier identification of the disease and paving the way for improved treatments.
Guest author: Solène Grosdidier, PharmD, PhD
This article was written as part of a series of ‘journal club’ summaries for Scientific Writers Ltd., and is based on the following publication:
First Author: Simuni T, et al.
Journal: The Lancet Neurology
Date online: February 2024
Other references:
Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson Disease Dementia
