Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Usefulness of α-synuclein as a Marker for Early Diagnosis of Parkinson's Disease in Skin Biopsy.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01380899
Recruitment Status : Completed
First Posted : June 27, 2011
Results First Posted : May 25, 2021
Last Update Posted : May 25, 2021
Sponsor:
Information provided by (Responsible Party):
Ildefonso Rodriguez-Leyva, Universidad Autonoma de San Luis Potosí

Study Type Observational
Study Design Observational Model: Case-Control;   Time Perspective: Cross-Sectional
Conditions Parkinson Disease
Parkinsonian Disorders
Intervention Procedure: Biopsy of skin
Enrollment 87
Recruitment Details Skin retro auricular biopsies were taken from 67 patients and 20 controls. The biopsies underwent immunohistochemistry (IHC) and immunofluorescence (IF) testing for a-synuclein, after which its presence was quantified as the percentage of positive cells (containing alpha-synuclein). Patients were divided into those with Parkinson's Disease (PD: 34) and those with Atypical Parkinsonism (AP: 33). AP patients included AP with neurodegenerative disease (proteinopathies) and secondary AP
Pre-assignment Details

PD used the United Kingdom PD Society Brain Bank. Lewy body dementia (LBD) used the consortium report on the DLB international workshop.

AD used the recommendations from the National Institute on Aging and Alzheimer's Association workgroups on diagnostic guidelines for AD.

MSA used the Second consensus statement on the diagnosis of multiple system atrophy.

PSP used the report of the NINDS-SPSP International Workshop.

Arm/Group Title Parkinson Disease Atypical Parkinsonism Control Group
Hide Arm/Group Description Patients with Parkinson Disease (PD) PD is the patient initially presented asymmetric onset (with both rest and postural tremors with a frequency of between 5 and 7 Hz), rigidity, bradykinesia, postural instability, an acceptable and sustained response to levodopa, and previous and concomitant nonmotor characteristic semiology.

AP was divided into primary (neurodegenerative) and secondary (postencephalitic, vascular, drug-induced, toxic) groups.

The neurodegenerative included patients with the diagnosis of Lewy body dementia (LBD) used the consortium report on the DLB international workshop.

Patients with the diagnosis of AD used the recommendations from the National Institute on Aging and Alzheimer's Association workgroups on diagnostic guidelines for AD.

Patients with the diagnosis of MSA used the Second consensus statement on the diagnosis of multiple system atrophy.

The diagnosis PSP used the report of the NINDS-SPSP International Workshop. CBS and we included a case with a diagnosis of neurodegeneration with brain iron accumulation syndrome (NBIA).

Most of these criteria are summarized in the SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders.

Subjects apparently in a good state of health without antecedents of neurodegenerative diseases and not symptoms or signs of neurodegeneration (comparable with the group's problem in gender, age, and population characteristics).
Period Title: Overall Study
Started 34 33 20
Completed 34 33 20
Not Completed 0 0 0
Arm/Group Title Parkinson Disease Atypical Parkinsonism Control Group Total
Hide Arm/Group Description Patients with Parkinson Disease: 34 Average. Age (mean SD) 66.82 (+11.4) Participants with Atypical Parkinsonism degenerative (26) or secondary (7), total: 33 Subjects without neurodegenerative disease and apparently good state of health (20) Total of all reporting groups
Overall Number of Baseline Participants 34 33 20 87
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 33 participants 20 participants 87 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
28
  82.4%
26
  78.8%
10
  50.0%
64
  73.6%
>=65 years
6
  17.6%
7
  21.2%
10
  50.0%
23
  26.4%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 34 participants 33 participants 20 participants 87 participants
66.82  (11.4) 68.2  (13.5) 74  (7.9) 69.6  (10.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 33 participants 20 participants 87 participants
Female
10
  29.4%
11
  33.3%
11
  55.0%
32
  36.8%
Male
24
  70.6%
22
  66.7%
9
  45.0%
55
  63.2%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Mexico Number Analyzed 34 participants 33 participants 20 participants 87 participants
34
 100.0%
33
 100.0%
20
 100.0%
87
 100.0%
1.Primary Outcome
Title Demonstrate the Presence of Alpha-Synuclein Inclusions in the Skin of Parkinson's Disease and Compare With an Atypical Parkinsonism Group and With a Healthy Control Group.
Hide Description

The presence in the brain of a-synuclein containing Lewy neurites, or bodies, is the histological hallmark of Parkinson's disease (PD).

The discovery of alpha-synuclein aggregates in nerve endings of the heart, digestive tract, and skin has lent support to the concept of PD as a systemic disease.

First, our goal was to demonstrate the presence of alpha-synuclein inclusions in the skin of PD patients.

Second, to detect quantitative differences (measures in the percentage of presence in the skin´s cells) between patients with PD, atypical parkinsonism (AP), compared with an apparent healthy group.

Time Frame An average of seven days.
Hide Outcome Measure Data
Hide Analysis Population Description
PD diagnosis is made if bradykinesia is associated with rigidity, tremor, or postural instability and unilateral onset and persistent asymmetry, excellent response to levodopa, severe levodopa-induced dyskinesia, and progression. AP are other neurodegenerative diseases with parkinsonism or related to strokes, head injuries, encephalitis, neuroleptic use, toxins, cerebral tumor, hydrocephalus. The Control group was a comparable population without parkinsonism and apparently healthy.
Arm/Group Title Parkinson Disease Atypical Parkinsonism Control Group
Hide Arm/Group Description:
Patients with the clinical diagnosis of Parkinson Disease
Atypical parkinsonian conditions mainly comprise progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multisystem atrophy (MSA), and dementia with Lewy bodies (DLB). Apart from these sporadic neurodegenerative disorders, atypical parkinsonism has also been described in various other inherited degenerative conditions such as frontotemporal dementia (FTD), Alzheimer's disease, and Perry syndrome. Nondegenerative parkinsonisms include vascular, toxic (use of neuroleptics, exposure to manganese, carbon monoxide, etc.), and traumatic.
Apparently, healthy subjects without a family history of neurodegenerative or chronic diseases could have population characteristics comparable to the problem groups' participants.
Overall Number of Participants Analyzed 34 33 20
Median (95% Confidence Interval)
Unit of Measure: percentage of expression
Epidermis. Alpha synuclein expresion
57.9
(44.9 to 62.6)
6.9
(0 to 18.3)
0
(0 to 1.7)
Pilosebaceus unit
62.1
(48.5 to 71.2)
7.7
(0 to 20.7)
0
(0 to 0)
Eccrine gland
58.4
(47.4 to 69.3)
0
(0 to 0)
0
(0 to 0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Parkinson Disease, Atypical Parkinsonism, Control Group
Comments The patients were stratified according to the clinical diagnosis made on the basis of the clinical findings, the MRI, and the progression of the disease. Both the clinical diagnosis and the semiquantitative histological analysis were carried out independently and blind to each other. The presence of aggregates of abnormal a-synuclein, expressed as the percentage of cells with positive inclusions in each experimental group, was tested for normality with the Shapiro-Wilk test.
Type of Statistical Test Superiority
Comments IHC analyses revealed intense α-synuclein positive immunostaining in PD patients, showing small nodular deposits from 1 to 2 μm in diameter in the SCL of the epidermis including the epidermal component adjacent to hair follicles, and in cells from PSUs, while control subjects presented null immunoreaction. The α-synuclein inclusions in the two groups of patients were morphologically similar but quantitatively different. These inclusions appeared to be juxtanuclear.
Statistical Test of Hypothesis P-Value < 0.01
Comments The presence of alpha-synuclein aggregates expressed as % of cells with inclusions was tested for normality (Shapiro-Wilk test). Then, with the nonparametric Kruskal-Wallis followed by Mann-Whitney U tests (software Statistica 7.0 at 95% confidence).
Method Kruskal-Wallis
Comments The groups were analyzed with Kruskal-Wallis followed by Mann-Whitney U tests.
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value 57.9
Confidence Interval (2-Sided) 95%
44.9 to 62.6
Parameter Dispersion
Type: Standard Deviation
Value: 8.85
Estimation Comments The expression of the abnormal protein (alpha-synuclein) must be different between the three groups (PD, AP, and control)
Other Statistical Analysis The patients were stratified according to the clinical diagnosis based on the clinical findings, the MRI, and the progression of the disease. Both the clinical diagnosis and the semiquantitative histological analysis were carried out independently and blind to each other. The presence of aggregates of abnormal α-synuclein, expressed as the percentage of cells with positive inclusions in each experimental group, was tested for normality with the Shapiro-Wilk test. Next, the groups were analyzed with the nonparametric Kruskal-Wallis followed by Mann-Whitney U tests. One independent analysis was performed for each structure, namely the epidermis, PSU, and EG. Assessments were performed using the software Statistica 7.0 (Tulsa, OK) at 95% confidence.
Time Frame The participants were aware of the possibles adverse events that they could present (pain and bleeding in the site where the biopsy was talked) during the seven days following the biopsy.
Adverse Event Reporting Description

Three possible EA were systematically advertised to the patients:

  1. Pain in the retro-auricular area where the biopsy was taken.
  2. Bleeding in the site of the biopsy.
  3. A potential danger of infection in the place of the biopsy. All of them are graduated as AE grade 1, according to the CTCAE. No one event serious event was reported.
 
Arm/Group Title PD (n = 34) Atypical Parkinsonism (n=33) Control Group (n=20)
Hide Arm/Group Description We enrolled 34 participants who had PD. A total of 33 patients had AP: from they 26 were found to have a neurodegenerative disease clinically (18 had a synucleinopathy-related diagnosis: MSA, LBD, and 8 had tauopathies: PSP, AD). We also included seven patients with secondary parkinsonism. A control group (n = 20) of similar age and sex distribution to the patient population was included. There was no significant difference in either age or evolution of disease between the two groups with parkinsonism.
All-Cause Mortality
PD (n = 34) Atypical Parkinsonism (n=33) Control Group (n=20)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/34 (0.00%)   0/33 (0.00%)   0/20 (0.00%) 
Hide Serious Adverse Events
PD (n = 34) Atypical Parkinsonism (n=33) Control Group (n=20)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/34 (0.00%)   0/33 (0.00%)   0/20 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
PD (n = 34) Atypical Parkinsonism (n=33) Control Group (n=20)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/34 (2.94%)   1/33 (3.03%)   0/20 (0.00%) 
Skin and subcutaneous tissue disorders       
Transient bleeding  1 [1]  1/34 (2.94%)  1/33 (3.03%)  0/20 (0.00%) 
1
Term from vocabulary, CTCAE (5.0)
Indicates events were collected by systematic assessment
[1]
Transient bleeding that stops with local biopsy site compression.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Ildefonso Rodriguez-Leyva
Organization: Facultad de Medicina, Universidad Autonoma de San Luis Potosi
Phone: +52 4442043016
EMail: ildefonso.rodriguez@uaslp.mx
Publications of Results:
Layout table for additonal information
Responsible Party: Ildefonso Rodriguez-Leyva, Universidad Autonoma de San Luis Potosí
ClinicalTrials.gov Identifier: NCT01380899    
Other Study ID Numbers: UASLP-PD001
First Submitted: June 17, 2011
First Posted: June 27, 2011
Results First Submitted: November 4, 2020
Results First Posted: May 25, 2021
Last Update Posted: May 25, 2021