New Method for Diagnosing Parkinson’s & Related Disorders

An aging population is a double-edged sword. On one hand, it indicates improved healthcare and longevity; on the other, it brings an increased prevalence of age-related challenges, particularly neurodegenerative disorders like parkinsonian disorders, named after Parkinson’s disease (PD). Among parkinsonian disorders, synucleinopathies stand out due to their impact on motor, non-motor, and cognitive functions. This group, primarily consisting of PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), is characterized by the abnormal accumulation of a protein called α-synuclein within the nervous system. α-Synuclein is a protein in the brain with important physiological functions, but in these disorders, it folds on itself and attaches to other proteins, creating sticky clumps that disrupt brain function. Two other disorders, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are similar but involve a protein called tau, instead of α-synuclein.

The diagnostic landscape of synucleinopathies is fraught with challenges, as PD, DLB, MSA, PSP, and CBS all often initially present with the triad of bradykinesia (slowness of movement), rigidity, and tremor. Despite these shared motor symptoms, each disorder diverges significantly in its pathophysiology as it progresses. PD manifests early with motor symptoms and later with cognitive impairment, DLB with severe cognitive impairment and hallucinations, and MSA with severe autonomic failures such as issues with blood pressure and sexual dysfunction. PSP typically leads to problems with balance and eye movement, and CBS to asymmetric limb rigidity and difficulty with coordinated movements. These distinct pathophysiological profiles are crucial to recognize because they mean that a one-size-fits-all approach to treatment is ineffectual. It is important to note that these disorders have subtypes, and may share more than parkinsonian symptoms, including sleep and psychiatric abnormalities. 

Precisely differentiating among these disorders currently hinges on examination of the brain after death, underscoring the urgent need for accurate diagnostic tools during a patient's life. However, current efforts are promising. The ability to at least separate synucleinopathies (PD, DLB, and MSA) from tauopathies (PSP and CBS) represents a significant diagnostic achievement and provides a clearer direction for patient management and research into effective treatments. This progress is vital because pinpointing the exact disorder is key to proper treatment and care.

 Current Biomarkers for Synucleinopathies

Clinicians rely on biomarkers – biological indicators found in tissue collected via a biopsy – to diagnose illnesses. When diagnosing synucleinopathies, they look for biomarkers by examining brain scans, cerebrospinal fluid (CSF), and blood tests.

 1. Neuroimaging Techniques: Techniques like the Dopamine Transporter (DaT) scan are particularly useful in identifying the loss of dopamine neurons, a feature in synucleinopathies. While an MRI can show structural changes in the brain, a DaT scan provides more specific evidence related to these conditions.

2. Cerebrospinal Fluid Analysis: The presence of abnormal α-synuclein species in CSF is a key marker for synucleinopathies. Elevated total α-synuclein or decreased β-amyloid/tau to α-synuclein ratios in the CSF are also supportive of a diagnosis.

3. Blood Biomarkers: Research is ongoing to determine whether certain forms of α-synuclein in blood may serve as potential markers. Challenges remain in distinguishing the pathological forms of α-synuclein from the normal ones circulating in the blood, but this is an active area of investigation.

 4. Extracellular Vesicles: Cells secrete extracellular vesicles, small membrane bubbles that contain important molecules reflecting the status of the parent cell, for many purposes. But despite initial enthusiasm, recent studies have cast doubt on the use of extracellular vesicles as a reliable source of biomarkers for synucleinopathies. The issues stem from contradictory study results, potential publication bias, and inconsistencies in collection and analysis methods.

 Seed Amplification Assays for Synucleinopathies

Seed amplification assays (SAAs) represent a pivotal breakthrough in detecting synucleinopathies. By pinpointing abnormal α-synuclein aggregates in the cerebrospinal fluid (CSF) known to cause PD, DLB, and MSA, SAAs offer a more definitive approach to diagnosis. The advantage of SAAs lies in their ability to detect the presence of synucleinopathies with a high degree of certainty, due to the characteristic increase in misfolded α-synuclein proteins. This is particularly helpful in confirming a synucleinopathy in patients, as traditional methods can be inconclusive.

With the advent of SAAs, clinicians can now more confidently diagnose these conditions, differentiating them from other neurodegenerative disorders such as PSP and CBS that do not exhibit the same α-synuclein pathology. This is a significant step in ensuring that patients receive the correct diagnosis early, particularly in the early stages of their disease course, which is critical for timely and appropriate treatment intervention. The specificity of SAAs also aids in accurately selecting participants for clinical trials, potentially speeding up the development of new treatments against α-synuclein.

Ongoing research aims to refine SAAs further, reducing the invasiveness of sample collection by exploring options such as nasal swabs, skin biopsies, or blood tests. For example, currently, samples of CSF are collected by lumbar puncture, which can be labor-intensive and invasive, and may lead to potential side effects. These advancements in SAAs are enhancing our ability to diagnose and manage synucleinopathies effectively, marking a new era in the care of neurodegenerative disorders.

Written by Hash Brown Taha

Edited by Robert Hubbard.

References

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