Decipher the biomarker characteristics of different clinical subtypes of Parkinson's disease!

*For medical professionals only

In modern society, neurological disorders are the leading cause of disability worldwide, with Parkinson's disease (PD) growing the fastest [1].

With an aging population and increasing industrialization, PD is a non-communicable disease that has become a global pandemic
.

At present, PD has become the second most common neurodegenerative disease
in the world.
From 1990 to 2015, the number of people with PD increased by 118% globally to 6.
2 million [1].

The global prevalence of PD is expected to double again to more than 17 million by 2040 [2].

More worryingly, from 1990 to 2016, the prevalence of PD in China was more than double that of any other country [3], and seeking diagnosis and treatment strategies for PD is an urgent need
to achieve a healthy China.

The clinical manifestations of PD often overlap with other neurodegenerative diseases, and current diagnostic indicators or biomarkers still cannot definitively diagnose
PD at an early stage.
In order to improve the accuracy of PD diagnosis, the clinical diagnostic criteria for PD are constantly improving
.
However, due to the significant heterogeneity of symptoms and outcomes of PD, the accurate diagnosis and treatment of PD pose severe challenges [4].

At present, identifying the different clinical subtypes of PD is one of the three major clinical research priorities in the field of PD research [5].

Different clinical subtypes of PD usually predict different clinical manifestations, potential pathological mechanisms and prognosis, so clearly defining different clinical subtypes of PD is a prerequisite
for personalized treatment of PD patients.
However, the clinical classification of PD at this stage is mainly based on clinical data, such as exercise, non-motor symptoms and demographic characteristics, and there is still a lack of genetic indicators
that may affect the clinical heterogeneity of PD.

Recently, a research team led by Eng-King Tan and Louis C.
S Tan of Duke-NUS School of Medicine published important research results in the journal NPJ Parkinson's Disease [6], clarifying the different subclinical classifications of PD and revealing the possible mechanism of PD heterogeneity, which provides a clinical reference
for achieving more targeted personalized treatment of PD.

Screenshot of the front page of the paper

Let's take a look at how this study is carried out
.

In a multicenter Asian cohort containing 206 PD patients, they performed hierarchical cluster analysis based on clinical features, genetic indicators and blood biochemical markers, and divided PD into three clinical subtypes
: A, B and C.
Subtype A (severe, severe motor and non-motor impairment with cognitive impairment), subtype B (intermediate, mild non-motor symptoms with cognitive impairment), and subtype C (mild, young age of onset without cognitive impairment).

Among them, patients with subtype A show the most serious functional impairment in terms of exercise, non-motor symptoms and cognition, and the underlying pathological mechanism may be that dopaminergic and non-dopaminergic pathways are involved in the lesion process
at the same time in the early stage of onset.
Subtype B is a unique subtype in which patients with subtype B do not have cognitive scores that do not coincide
with non-motor symptom scores.
The mechanism of cognitive impairment in PD patients is not fully understood, and abnormal function of acetylcholine neurotransmitters is one of
the possible mechanisms.
Subtype C is characterized by a young onset and generally performs better in motor, non-motor, and cognitive areas, a finding consistent with previous studies [7].

Figure 1.
Parkinson's disease Singapore longitudinal cohort (PALS) hierarchical clustering treemap

First, in terms of clinical features, there were significant differences in age among the clinical subtypes of these three PDs, with the mean ages of subtypes A, B and C being 69.
6 ± 7.
9, 63.
6 ± 7.
4 and 59.
4 ± 9.
7 years
, respectively.
At the same time, the three subtypes also differed
significantly across all cognitive scores, most motor scores, and most non-motor symptom scores.

Subtype A is most severe in cognitive, motor, and non-motor symptoms, while systolic blood pressure drops are most common
in subtype A.
Subtype B presents with moderate non-motor symptoms and cognitive impairment, with cognitive function scores ranging between
subtypes A and C .
Subtype C is a clinical subtype with a younger age of onset, the mean age of diagnosis is significantly lower than the other two subtypes, and patients with this subtype have good cognitive performance
.
There were no significant differences
between the three subtypes in genetic risk score (PRS), anxiety and depression score (HADS), and rapid eye movement sleep disorder (RBD).

Secondly, the analysis of PD-related single gene polymorphisms (SNPs) in Asian populations showed that among the 206 PD patients, the distribution frequency of Park16 rs6679073 A allele was 76.
7%, and the distribution frequency of SV2C rs246814 T allele was 15.
0%.

Park16 rs6679073 A and SV2C rs246814 T had significant distribution differences
in three clinical subtypes: A, B and C.
Park16 rs6679073 Allele carriers accounted for 67%, 74% and 89% of the A, B, and C subtypes, respectively.
SV2C rs246814 T alleles accounted for 7%, 12% and 25%.

Therefore, the Park16 rs6679073 A allele and the SV2C rs246814 T allele may be important genetic biomarkers for differentiating different clinical subtypes of PD, while also suggesting that these two SNPs may have potential neuroprotective effects
in our Asian cohort.

Table 1.
Allele distribution of Asian PD-associated genes in three clinical subtypes of PD

Finally, in terms of blood biological indicators, after adjusting for factors such as diagnosis age, sex and hypertension, hyperlipidemia, lipid-modifying drugs and antihypertensive drugs, homocysteine (Hcy) and C-reactive protein (CRP) plasma levels still differ
significantly among the three subtypes.
Homocystis and CRP plasma levels are highest in subtype A and lowest
in subtype C.
Therefore, Hcy and CRP are expected to be blood biomarkers for the identification of severe PD
.

Previous studies have shown a strong relationship between Hcy and cognitive function in patients with PD [8].

But this study found that elevated homocystic levels correlate closely with disease severity in PD, which may open up new ideas
for PD treatment.
Therefore, it is worth investigating whether Hcy levels can be reduced by vitamin supplementation and thus the severity
of PD.
At the same time, CRP is another reliable biomarker for severe PD subtypes, suggesting a possible hyperinflammatory state
in severe PD subtypes.

In summary, the study of Eng-King Tan and Louis C.
S Tan et al.
is based on PD cohort studies in Asian populations, clearly defines different clinical subtypes of PD, and explores their potential pathophysiological differences, which will help reveal the underlying mechanism of PD heterogeneity and develop more effective personalized treatment
of PD.
However, the study was a cross-sectional study with no longitudinal follow-up of different clinical subtypes of PD, and blood biomarkers were not continuously tested, so the relationship
between these biomarkers and PD progression could not be demonstrated.
In future studies, genetic and biochemical differences between different clinical subtypes of PD are needed to further validate and evaluate the impact
of these biomarkers on PD progression.
At the same time, the authors also propose that their conclusions are based on a single cohort study only, with a limited sample size, and need to be further validated
in other populations.

With the rapid development of modern medicine, we believe that PD will evolve from a disease that relies solely on clinical features for diagnosis to a disease
supported by biomarkers.
Early and accurate diagnosis of PD will be just around
the corner.
Future neuropathologists may no longer see PD as a single disease, but will be able to confidently diagnose different clinical subtypes of PD and accurately judge their response and prognosis
.

References:

[1].
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Lancet Neurol.
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doi:10.
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[2].
Dorsey ER, Sherer T, Okun MS, Bloem BR.
The Emerging Evidence of the Parkinson Pandemic.
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2018; 8(s1):S3-S8.
doi:10.
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[3].
GBD 2016 Parkinson's Disease Collaborators.
Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016 [published correction appears in Lancet Neurol.
2021 Dec; 20(12):e7].
Lancet Neurol.
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[4].
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2021; 20(5):385-397.
doi:10.
1016/S1474-4422(21)00030-2

[5].
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Ann Neurol.
2014; 76(4):469-472.
doi:10.
1002/ana.
24261

[6].
Deng X, Saffari SE, Liu N, et al.
Biomarker characterization of clinical subtypes of Parkinson Disease.
NPJ Parkinsons Dis.
2022; 8(1):109.
Published 2022 Aug 29.
doi:10.
1038/s41531-022-00375-y

[7].
van Rooden SM, Heiser WJ, Kok JN, Verbaan D, van Hilten JJ, Marinus J.
The identification of Parkinson's disease subtypes using cluster analysis: a systematic review.
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[8].
de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD.
Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial.
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doi:10.
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2758

The author of this articleHe Qinqin

Responsible editorDai Siyu