Application of sensory nerve quantitative tests to analyze the subtypes of motor disorders in Parkinson’s disease

Abstract

This study investigated the sensory nerve function in people with different subtypes of Parkinson’s disease (PD), which included the tremor-dominant (TD) group (n = 30), postural instability and gait disorder (PIGD) group (n = 33), and healthy-controls (HC) group (n = 33). Sural nerve's current perception threshold (CPT) and pain tolerance threshold (PTT) in both feet were measured at different frequencies. Results were evaluated using the mini-mental state examination (MMSE), Hoehn Yahr scale (H-Y) , and 3-meter timed-up-and-go-test (TUGT). The MMSE scores of the TD and HC groups were higher than those of the PIGD group (TD < HC). The 3-meter TUGT scores of the PIGD group were higher than theTD and HC groups (TD > HC). The PIGD patients experienced a significantly shorter disease duration and higher H-Y score than the TD patients (P < 0.05). The values of 2 KHz CPT of left-side (CPTL), 2KHz CPT of right-side (CPTR), and 5 Hz CPTR in the PIGD group were significantly higher compared to the TD and HC groups (P < 0.05, Bonferroni correction). Additionally, the values of 250 Hz CPTL, 5 Hz CPTL, 250 Hz CPTR, 2 kHz PTT of left-side (PTTL), 250 Hz PTTL, and 5 Hz PTTL in the PIGD group were significantly elevated relative to the TD group (P < 0.05, Bonferroni correction). Distinctive current threshold perception and PTT of the sural nerve can be observed in patients with varying PD subtypes, and sensory nerve conduction threshold electrical diagnostic testing can detect these discrepancies in sensory nerve function.

Introduction

Parkinson’s disease (PD), with a concealed onset, is a neurological condition of the central nervous system that follows Alzheimer’s disease in terms of prevalence [1]. Globally, more than 6 million people are suffering from PD [2,3]. The rate of PD increases with age, and the prevalence rate of PD among individuals aged 65 and above in China is 1700/100 000. With increasing longevity in China, the rate of PD is also rising. By 2030, there will be 5 million PD patients in China, which will be a significant burden on families and society [4].

PD is a highly heterogeneous condition [5,6], which is caused by the aggregation of α-synuclein proteins in neurons [7], resulting in a considerable decrease of dopaminergic neurons in the substantia nigra. This results in motor symptoms such as delayed movement, muscle rigidity, static tremors, and postural gait disorders, as well as a range of non-motor symptoms (NMS), including decreased olfaction, sensory disturbances, emotional disturbances, sleep disturbances, cognitive impairment, and constipation [8,9]. PD is usually divided into two subtypes based on motor symptoms: tremor dominant (TD) and posture instability gait disorder (PIGD) [10]. Patient groups with different subtypes of PD can vary in terms of onset age, disease progression rate, responsiveness to dopamine replacement therapy, and accompanying NMS [11,12]. Those with PIGD tend to have more severe neurological damage, more complex clinical manifestations, and a poorer response to treatment with levodopa and deep brain electrical stimulation.

A quantitative measurement method, sensory nerve quantitative tests, has been developed recently and takes advantage of electrical stimulation to quantify sensory nerve function [13]. It is characterized by its high objectivity, neural selectivity, and the capability to detect the functional integrity of more than 90% of sensory nerves with specific electrical stimulation, including the advantages of myelinated and unmyelinated fibers of different sizes. This method has been employed in clinical and scientific research [14].

Therefore, we used the Neurometer/C sensory nerve quantitative detector to gauge the conduction and performance of three types of sensory nerve fibers (coarse myelinated, fine myelinated, and unmyelinated) to measure the current perception threshold (CPT) and pain tolerance threshold (PTT) of the sural nerve in PD patients with different motor subtypes. Additionally, we used scales to evaluate PD patients’ motor and NMS to determine if any variations in sensory nerve function exist among the different motor subtypes of PD, thereby deepening our understanding of PD motor subtypes.

Materials and methods

Patients

This cross-sectional study encompassed 96 patients who were treated at Jiangsu Provincial People’s Hospital from June 2020 to December 2020, comprising of 30 in the TD group, 33 in the PIGD group, and 33 healthy caregivers as the healthy control group (HC group). The inclusion criteria for TD group and PIGD group meeting the PD diagnostic criteria established by the UK Parkinson’s Disease Brain Bank [15]. The exclusion criteria included individuals with diabetes, lumbar disc herniation, peripheral nervous system diseases, deep brain stimulation (DBS), pacemakers, spinal cord implants, peripheral nerve stimulators, secondary Parkinson’s syndrome, Parkinson’s superimposed syndrome, depression, dementia, schizophrenia, and those unable to cooperate.

Equipment

All PD patients and HC group participants were subjected to standardized, automated testing utilizing the Neurometer CPT/C detector in a quiet room with a relative humidity below 80% and a room temperature of approximately 26 °C. The sensory threshold of the predetermined innervated area of the lateral gastrocnemius nerve in the subjects was detected by electrode stimulation at 2KHz, 250 Hz, and 5 Hz. The minimum value that can cause a painless sensation, measured in the sensory threshold measurement mode, was used as CPT. In the PTT measurement mode, the stimulation intensity increased from 0.01 milliampere to 9.99 milliampere constant current sine wave electrical stimulation, and the maximum value of pain that could be tolerated was used as PTT. After a preliminary experimental threshold was determined, alterations were made in the vicinity of the assumed threshold to ascertain the stability and reproducibility of the threshold. The results were then confirmed via placebo stimulation, which switched off all currents without informing the patient, thus demonstrating the missing stimuli. To determine the last threshold, a uniform response from patients is required, with the test results being shown in CPT and PTT and printed in a standard format. The entire procedure required 15-20 min to complete. All participants and their families were notified of the study and consented to participate voluntarily. No reports of any negative reactions or injuries due to the quantitative detection of sensory nerves in research have been reported [16].

Clinical information

Twelve hours after their medication was terminated, an assessment was conducted on patients with PD using the Unified Parkinson’s Disease Rating Scale (UPDRS). Based on the ratio of their mean tremor score to their mean postural instability gait disorder score in the UPDRS score, they were divided into two groups. If the ratio was ≥ 1.5, they were classified as the TD group, and if the ratio was ≤ 1.0, they were classified as the postural instability gait disorder (PIGD) group. Additionally, they underwent the 3-meter timed-up-and-go-test (TUGT), freezing of gait questionnaire (FOGQ), mini-mental state examination (MMSE), PD sleep scale (PDSS), Epworth sleepiness scale (ESS), fatigue severity scale (FSS), REM sleep behavior disorder screening questionnaire (RBDSQ), Hamilton depression rating scale (HAMD), Hamilton Anxiety Scale (HAMA), and PD Questionnaire (PDQ-39). The Scales for Outcomes in PD-Autonomic questionnaire (SCOPA-AUT) score was also recorded, as well as the patient’s medical history information such as age, gender, education level, height, weight, and course of disease. The severity of the disease was classified using the improved Hoehn Yahr scale (H-Y) staging [17], with stages 1–2.5 being considered early PD and stages 3–5 as mid to late PD. Data was also collected from the healthy control group, including baseline data, CPT, PTT, and scale scores.

Statistical analysis

Data processing and analysis was conducted using SPSS 25.0 statistical software. The Shapiro-Wilk’s normality test was first conducted for count data. When the data conformed to a normal distribution, the one-way ANOVA with Bonferroni was used; if not, then the non-parametric Kruskal–Wallis and Mann–Whitney U tests were administered. A pairwise comparison (corrected by Bonferroni) was done for data with statistical differences between the three groups. Additionally, chi-square tests were employed for categorical data (gender). A P-value of less than 0.05 indicated a statistically significant difference.

Results

Clinical baseline characteristics

This study included a total of 63 PD patients and 33 healthy controls. The PD group was divided into 30 patients with TD and 33 with PIGD. Twenty-one were in the early stage, and 9 in the middle and late stages of Hoehn-Yahr staging in the TD group, with a duration of 6–120 months. Fourteen were in the early H-Y stage, and 19 were in the middle and late stages in the PIGD group with a span of 2–84 months. There was no statistically significant difference in the number of enrolled cases, gender, age, and weight among the three groups (P > 0.05) (Table 1).

Table 1.

Pairwise comparisons of clinical baseline among HC, TD, and PIGD groups

	HC (n = 33)	TD (n = 30)	PIGD (n = 33)	Test value	P value
Cases (M/F)	33 (12/21)	30 (11/19)	33 (17/16)	2.01	0.37b
Age (year)	58.1 ± 11.5	62.1 ± 14.5	61.2 ± 11.3	2.61	0.27c
Body weight (Kg)	61.7 ± 9.0	58.0 ± 9.2	63.7 ± 9.5	3.03	0.05a,d
Height (cm)	166.0 ± 6.5	164.2 ± 8.3	165.7 ± 7.5	0.54	0.59d

HC, healthy control; PIGD, postural instability and gait difficulty; TD, tremor-dominant.

^aP < 0.05 indicates a statistically significant difference.

^bChi-square test.

^cNonparametric Kruskal–Wallis test.

^dOne-Way ANOVA.

Comparison of clinical scales

The MMSE scores of the PIGD group were lower than those of the TD and HC groups, with the TD group having a lower score than the HC group; the TUGT of the PIGD group was greater than that of the TD and HC groups, with the TD group having a higher score than the HC group; the duration of the disease in the PIGD group was shorter than that of the TD group, and these differences were statistically significant (P < 0.05). Patients with PIGD showed a higher score on the H-Yscale assessment than those with TD subtypes. Nevertheless, no considerable distinctions (P > 0.05) were seen in FOGQ, PDSS, ESS, RBDSQ, HAMD, HAMA, PDQ-39, and SCOPA-AUT (Table 2).

Table 2.

Comparisons of clinical scores among HC, TD, and PIGD groups

	HC	TD	PIGD	F	P value	Post-hoc pairwise comparison (Bonferroni adjusted P-value)
MMSE	27.5 ± 2.1	25.2 ± 3.5	23.6 ± 3.6	20.63	<0.001a,b	PIGD vs. TD: <0.001; PIGD vs. HC: 0.02; TD vs. HC: 0.36
TUGT	6.4 ± 0.8	12.63 ± 7.05	20.5 ± 8.8	56.68	<0.001a,b	PIGD vs. TD: 0.01; PIGD vs. HC: <0.001;TD vs. HC: <0.001
Course	-	52.3 ± 39.0	30.1 ± 23.0	-2.23	0.03a,c
UPDRS Score	-	42.3 ± 17.4	41.7 ± 14.9	0.13	0.90d
FOGQ	-	7.3 ± 6.0	9.3 ± 6.2	-1.41	0.16c
Modified H-Y scale	-	2.0 ± 0.8	2.6 ± 0.8	-2.58	0.01a,c
PDSS	-	27.3 ± 17.8	28.1 ± 14.2	-0.19	0.85d
ESS	-	3.7 ± 3.9	5.5 ± 4.9	-1.65	0.10c
FSS	-	13.9 ± 10.6	18.3 ± 10.3	-1.94	0.05c
RBDSQ	-	3.5 ± 3.1	3.6 ± 2.9	-0.26	0.79c
HAMD	-	13.5 ± 7.6	11.8 ± 5.9	1.01	0.32d
HAMA	-	14.8 ± 7.0	12.4 ± 4.8	1.59	0.18d
PDQ-39	-	41.7 ± 27.3	55.2 ± 27.0	-1.97	0.05d
SCOPA-AUT	-	15.7 ± 9. 6	15.9 ± 9.5	-0.04	0.97c

‘- ’ indicates no score; ESS, Epworth sleepiness scale; FOGQ, Freezing of gait questionnaire; FSS, fatigue severity scale; HAMA, Hamilton anxiety rating scale; HAMD, Hamilton depression rating scale; HC, Healthy control; MMSE, mini-mental state examination; PDQ-39, Parkinson’s Disease Questionnaire (39-item); PDSS, Parkinson’s disease sleep scale; PIGD, Postural instability and gait difficulty; RBDSQ, REM sleep behavior disorder screening questionnaire; SCOPA-AUT, Scales for Outcomes in Parkinson’s Disease-Autonomic questionnaire; TD, Tremor-dominant; TUGT, Timed up and go test (3 meters); UPDRS, Unified Parkinson’s disease rating scale.

^aP<0.05 indicates a statistically significant difference.

^bNon-parametric Kruskal-Wallis test.

^cMann-Whitney u test.

^dTwo-sample T test.

Comparison of bilateral CPT and PTT

Results showed statistically significant differences in 2KHz CPTL, 250 Hz CPTL, 5 Hz CPTL, 2KHz CPTR, 250 Hz CPTR, 5 Hz CPTR, 2kHz PTTL, 250 Hz PTTL, and 5 Hz PTTL among the three groups (P < 0.05, Table 3). Following a post-hoc analysis, the values of 2KHz CPTL, 2KHz CPTR, and 5 Hz CPTR in the PIGD group were observed to be significantly higher compared with TD and HC groups (P < 0.05, Bonferroni correction). Furthermore, the values of 250 Hz CPTL, 5 Hz CPTL, 250 Hz CPTR, 2kHz PTTL, 250 Hz PTTL, and 5 Hz PTTL in the PIGD group were also significantly higher than those in the TD group (P < 0.05, Bonferroni correction). These results suggest that the sensory function of the bilateral lower limb sural nerve in the PIGD group was decreased. In comparison, there was no significant abnormality in the sensory part of the bilateral lower limb sural nerve in the TD group relative to the HC group.

Table 3.

Pairwise comparisons of bilateral CPT and PTT among HC, TD, and PIGD groups

	HC	TD	PIGD	F value	P value	Post-hoc pairwise comparison (Bonferroni adjusted P value)
2KHz CPTL	222.8 ± 53.6	217.3 ± 65.4	299.5 ± 127.8	11.58	0.003a,b	PIGD vs. TD: 0.01; PIGD vs. HC: 0.03;TD vs. HC: 1
250 Hz CPTL	68.8 ± 31.1	58.0 ± 29.9	87.6 ± 49.9	6.87	0.03a,b	PIGD vs. TD: 0.03; PIGD vs. HC: 0.59;TD vs. HC: 0.52
5 Hz CPTL	31.0 ± 14.3	29.7 ± 16.4	48.6 ± 31.5	8.70	0.01a,b	PIGD vs. TD: 0.02; PIGD vs. HC: 0.06;TD vs. HC: 1
2KHz CPTR	223.5 ± 55.6	216.9 ± 80.9	288.8 ± 109.5	12.00	0.002a,b	PIGD vs. TD: 0.003; PIGD vs. HC: 0.03;TD vs. HC: 1
250 Hz CPTR	62.0 ± 28.9	49.6 ± 30.3	86.9 ± 48.8	14.18	0.001a,b	PIGD vs. TD: 0.001; PIGD vs. HC: 0.10;TD vs. HC: 0.28
5 Hz CPTR	28.66 ± 14.9	31.0 ± 21.2	46.9 ± 24.5	11.99	0.002a,b	PIGD vs. TD: 0.01; PIGD vs. HC: 0.02;TD vs. HC: 1
2kHz PTTL	12.8 ± 5.0	11.1 ± 4.4	14.4 ± 4.8	6.95	0.03a,b	PIGD vs. TD: 0.03; PIGD vs. HC: 0.59;TD vs. HC: 0.51
250 Hz PTTL	8.2 ± 4.3	5.7 ± 1.5	8.4 ± 4.3	8.64	0.01a,b	PIGD vs. TD: 0.02; PIGD vs. HC: 1;TD vs. HC: 0.07
5 Hz PTTL	10.9 ± 6.0	7.5 ± 3.6	10.6 ± 5.9	7.47	0.02a,b	PIGD vs. TD: 0.04; PIGD vs. HC: 1;TD vs. HC: 0.06
2kHz PTTR	13.7 ± 5.3	11.3 ± 4.8	14.2 ± 4.5	5.79	0.06b
250 Hz PTTR	8.1 ± 4.5	6.4 ± 3.4	7.4 ± 3.7	3.69	0.16b
5 Hz PTTR	11.4 ± 7.4	9.3 ± 5.7	10.1 ± 5.7	0.93	0.63b

CPTL, current perception threshold of left-side; CPTR, current perception threshold of right-side; PTTL, pain tolerance threshold of left-side; PTTR, pain tolerance threshold of right-side.

^aP < 0.05 indicates a statistically significant difference.

^bNon-parametric Kruskal–Wallis test.

Discussion

This study is the first to employ a sensory nerve quantitative detector to evaluate the sensory nerve function of people with various motor subtypes of PD. In general, three distinct types of sensory nerve fibers exist, including thickly myelinated nerve fibers (A-β Fiber, diameter 5–15 μm), finely myelinated nerve fibers (A-δ Fiber, diameter 1–4 μm), and unmyelinated nerve fibers (C-fibers, diameter 0.5–1.5 μm). 80% of the protective sensations (touch, pain, temperature, etc.) are transmitted by C-fibers [18]. The sural nerve is purely sensory, and we used Neurometer to selectively activate sensory nerve fibers in the distribution area of the sural nerve at the fixed site on the lateral side of the feet; 2KHz stimulating A-β Fibers, 250 Hz stimulating A-δ Fibers, and 5 Hz stimulating C-fibers. This detection method is not limited by factors such as skin and mucosal thickness and has the advantage of having a high degree of repeatability [19].

This study examined the CPT and PTT results of 63 PD patients and 33 HC patients. It was revealed that the values of 2KHz CPTL, 250 Hz CPTL, 5 Hz CPTL, 2KHz CPTR, 250 Hz CPTR, 5 Hz CPTR, 2kHz PTTL, 250 Hz PTTL, and 5 Hz PTTL were substantially different among the three groups (P < 0.05). Specifically, the values of 2KHz CPTL, 2KHz CPTR, and 5 Hz CPTR were higher in the PIGD group than in the TD and HC groups (P < 0.05, Bonferroni correction). Moreover, the values of 250 Hz CPTL, 5 Hz CPTL, 250 Hz CPTR, 2kHz PTTL, 250 Hz PTTL, and 5 Hz PTTL in the PIGD group were also significantly higher compared with the TD group (P < 0.05, Bonferroni correction). The TD and HC groups did not demonstrate a substantial difference, indicating a decrease in the sensory function of the bilateral lower limb sural nerve in the PIGD group. These findings agree with previous studies [20–22], suggesting that PD patients may experience sensory nerve abnormalities during the disease, which can manifest as decreased, regular, or elevated CPT and PTT values. Therefore, the present results suggest that PIGD patients may have sensory nerve abnormalities compared to TD and HC patients.

Researchers discovered that peripheral nerve inflammation contributes to sensory abnormalities in PD patients after analyzing the electrophysiology and biopsy of the sural nerve in patients with and without sensory impairments [22]. This was accompanied by the activation of Schwann cells and inflammation [23], indicating that peripheral nerve inflammation is linked to PD sensory abnormalities’ physiological and pathological processes. It has been widely suggested that neuroinflammation and oxidative stress may be significant contributors to the development of PD. Nolano et al. have found evidence that those with PD suffer a substantial loss of free and unwrapped nerve endings, yet the underlying causes of this remain unknown [24]. Research suggests that the sensory system is involved in the pathophysiology and etiology of various motor disorders [25]. However, it is uncertain whether the differences in sensory abnormalities between PD subtypes are primary or secondary [26]. To gain a better understanding, further reliable investigations are needed to identify any potential pathogenic associations, which can provide more comprehensive treatment principles.

The MMSE score of the PIGD group was significantly lower than the scores of the TD and HC groups, as demonstrated by our findings (P < 0.05). There was no considerable difference between the TD and HC groups, indicating that cognitive impairment could be linked to PIGD but not TD. In addition, it was observed that the course of the disease and the H-Y grading differed notably between the TD and PIGD groups (P < 0.05). Yet no substantial distinction was observed in FOGQ, PDSS, ESS, RBDSQ, HAMD, HAMA, PDQ-39, and SCOPA-AUT, with all results statistically insignificant (P > 0.05). The PIGD group experienced a shorter period of the disease, a higher improvement in H-Y grading, and a higher TUGT. Additionally, there was a marked difference in TUGT between the two PD subtypes and the HC groups, indicating gait issues in PD patients. Those in the PIGD group likely have a faster progression of the illness, more pronounced signs of postural instability and gait problems, and more severe cognitive impairment. Moreover, the TD and PIGD groups differ in the incidence and subtypes of cognitive impairment, including lower cognitive status, poor semantic fluency score, and lower pentagon copying score [27]. Reports in the literature demonstrate that gait disorders in individuals with tremors as the initial symptom are in line with what has been documented [28]. Some scholars think that gait disorders in those with tremors as the primary symptom tend to have a less serious condition with a more favorable prognosis [29,30].

This research has certain limitations, such as a limited sample size, no further exploration of the differences in clinical intervention and treatment between the two groups, and the fact that CPT and PTT may be affected by various factors, such as gender and age [31]. It remains unclear what is causing the decreased sensory nerve function in PD patients and further research is needed.

To sum up, the CPT and PTT of the sural nerve demonstrate distinctions depending on the PD motor subtype. The use of sensory nerve conduction threshold electrical diagnostic tests to detect deviations in sensory nerve function between PD motor subtypes can give more insight into PD subtypes.

Acknowledgements

HT and YY: Conceptualization, Methodology, Validation, Investigation, Data curation, Resources, Writing original draft, Review & editing, Project administration. KZ: Conceptualization, Formal analysis, Investigation, Data curation, Writing original draft, Review & editing, Resources.

This study was approved by the ethical committee of The First Affiliated Hospital of Nanjing Medical University. Written informed consents were acquired from all the participants or their legal representative(s).

Conflicts of interest

There are no conflicts of interest.