Skin conditions in early Parkinson’s disease

Abstract

Objective:

Skin conditions have been associated with increased risk of Parkinson’s disease (PD). Little is known about clinical and biomarker differences according to presence of skin conditions among PD patients. Studying these differences might provide insight into PD pathogenesis.

Methods:

We examined the association between common skin conditions and risk of PD in a case-control study of 423 early drug-naïve PD cases and 196 healthy controls (HC) in the Parkinson’s Progression Markers Initiative (PPMI). Among PD participants, we examined if skin conditions were associated with clinical and PD-relevant biomarkers.

Results:

Skin conditions occurred more frequently among PD participants (41%) relative to HC (32%). In multivariate analyses, we observed an association between any skin condition and PD (OR = 1.49, 95% CI = 1.03–2.16) and basal cell carcinoma and PD (OR = 2.05, 95% CI = 1.02–4.08). PD participants who reported skin conditions were older (OR = 1.68, 95% CI = 1.21–2.35) more educated (OR = 1.70, 95% CI = 0.99–2.91), had higher Semantic Fluency Test (SFT) scores (OR = 1.45, 95% CI = 1.07–1.96) and Hopkins Verbal Learning Test (HVLT) retention scores (OR = 1.55, 95% CI = 1.09–2.22) compared to PD patients without skin conditions. None of the associations remained significant after Bonferroni correction for multiple comparisons.

Conclusions:

We observed a positive association between any skin condition as well as basal cell carcinoma and PD. PD participants with skin conditions were older, more educated, had higher SFT and HVLT retention scores compared to those without skin conditions. However, all associations were no longer significant after Bonferroni multiple comparisons correction. Observed associations should be confirmed in larger, longitudinal studies.

1. Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) leading to tremor, rigidity, bradykinesia and postural instability. The etiology of PD is attributed to a complex combination of genetic and environmental factors [1,2]. 5–10% of PD cases are attributed to specific genetic mutations and the rest are sporadic [1,3]. While motor dysfunction is the primary characteristic of PD pathology, non-motor symptoms such as cognitive impairment, gastrointestinal dysfunction, olfactory, skin and sleep disorders are also reported [1,4,5].

Prior studies have reported an association between skin conditions and PD [2,6–22]. Increased incidence of certain skin cancers is reported in PD [1,4,7–9,14]. Skin carcinoma and malignant melanoma were observed in PD participants and some preceded PD diagnosis [7,9,16]. Higher prevalence of preneoplastic, neoplastic and nonmelanoma skin cancers is reported in PD compared to HC [17]. The pigmentation pathway, which is associated with skin conditions, could also be involved in PD pathogenesis [7]. It is also hypothesized that peripheral inflammation leads to neuroinflammation and subsequent microglial activation associated with degeneration of DA neurons [2]. Chronic inflammatory skin conditions such as psoriasis have been associated with 38% increased risk of PD [10]. An increased incidence of PD in patients with rosacea has also been reported [11]. Shared genetic, environmental and immune patterns, mechanisms associated with Helicobacter pylori (H. pylori) infection and increased small intestinal bacteria are hypothesized as common etiological factors in rosacea and PD [11]. Conditions attributed to autonomic dysfunction such as seborrhea and seborrheic dermatitis are observed in PD and seborrheic dermatitis has been associated with an increased risk of PD [6,22]. Higher prevalence of other skin-related abnormalities, such as hyper-hidrosis or sweating, has also been reported in PD [6,13]. Furthermore, studies have reported loss of cutaneous nerve fibers and aggregation of α-synuclein specifically in sympathetic adrenergic and sympathetic cholinergic fibers in PD skin [13,19,21].

While skin conditions appear to be related to PD risk, little is known about whether and how PD participants differ, clinically or biologically, according to presence of skin conditions. Specifically, it has not been examined whether, in PD participants, presence of skin condition is associated with PD severity, cognitive function and other non-motor symptoms. Differences in PD severity between PD participants with versus without skin conditions may provide further evidence in favor of a biological relationship between skin disease and PD. Differences in cognition or other non-motor symptoms might provide evidence for skin health as a possible future marker to differentiate PD subtypes. Furthermore, in an attempt to understand the underlying biological mechanisms relating skin disease to PD, and to corroborate any differences in clinical features, we examined whether biomarkers relevant to PD, such as α-synuclein, differ in PD participants with versus without skin conditions. The Parkinson’s Progression Markers Initiative (PPMI) cohort provided an excellent opportunity to pursue these research questions because it has collected extensive data on clinical conditions and PD-relevant biomarkers.

2. Methods

2.1. Study participants

Data were obtained from the PPMI database (www.ppmi-info.org/data). PPMI is an observational, international, multicenter study aimed at identifying PD progression biomarkers and is a public-private partnership sponsored by the Michael J. Fox Foundation and other funding partners [23]. Data was downloaded from the PPMI database in October 2016. Data at baseline (BL) and on first screening visit (SC) on 423 recently-onset drug-naïve PD participants with dopamine transporter (DAT) deficits and complete enrollment dates and 196 HC with no significant neurological deficits, no first-degree relatives with PD and over 30 years of age were used for this analysis. Details on inclusion and exclusion criteria for PD participants and healthy controls (HC) in the PPMI have been described previously [23].

2.2. Ethics

The PPMI study was conducted in accordance with Good Clinical Practice (GCP) and International Conference on Harmonization (ICH) based on local, national and international guidelines. Ethics and regulatory details of the PPMI study are available at ppmi-info.org. We obtained IRB approval from the University of Massachusetts, Lowell IRB for the secondary analysis of the PPMI data.

2.3. Assessment of skin conditions

Participants reported their current medical conditions and medical history during screening visit. Presence of skin conditions in PD cases and HC was assessed from these records. We focused our analyses on the most prevalent inflammatory skin conditions which included eczema, psoriasis, rosacea (including ocular and acne rosacea), seborrheic skin conditions (including seborrhea, seborrheic dermatitis and seborrheic keratosis) and skin cancers such as melanoma, basal and squamous cell carcinomas. Less prevalent skin conditions including subtypes of acne, actinic keratosis, atopic dermatitis, benign cysts and skin growth, dermatitis, dry skin, herpes, sunspots etc. were categorized as ‘other skin conditions’. We then categorized PD patients according to presence of any skin condition.

2.4. Covariate assessment

A description of covariates used in this study is available in the PPMI operations manual at ppmi-info.org. Male and female participants over 30 years of age were eligible to enroll in the study and sex was recorded. Age and gender at birth were recorded at screening visit. PD duration was assessed after first PD diagnosis [24]. Education was treated as a binary variable (0 = 13 years of education and 1 = ≥ 13 years of education) [24]. Participants reported over-the-counter and prescription medications at the time of screening visit including brand name and/or generic name, total dose, frequency and route of administration. In our analyses, we considered nonsteroidal anti-inflammatory drug (NSAID) use as a covariate. NSAIDs reported in the PPMI included ibuprofen, naproxen, acetylsalicylic acid, celecoxib, diclofenac, meloxicam, eto-dolac, flurbiprofen, ketoprofen, nabumetone, piroxicam and rofecoxib. NSAID use was treated as a binary variable (0 = no NSAID use, 1 = NSAID use).

2.5. Assessment of clinical features

PPMI baseline demographics, motor and non-motor scores, and biomarker test values have been described previously [5,23,24]. Details of tests conducted for assessment of motor, non-motor and biomarker measures in the PPMI are available at ppmi-info.org. In the PPMI, PD severity was rated using Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts I, II, III and total scores and Hoehn and Yahr stage was obtained from MDS-UPDRS Part III. Sleep dysfunction was assessed with Rapid Eye Movement Behavior Disorder (RBD) questionnaire and Epworth Sleepiness Scale (ESS). Neurobehavior assessments included 15-item Geriatric Depression Scale-15 (GDS) and State and Trait Anxiety Inventory (STAI). Cognitive domains tested in the PPMI are described previously [5]. Global cognitive function was assessed by Montreal Cognitive Assessment (MoCA). Executive function and working memory were assessed by Semantic Fluency Test (SFT) and Letter Number Sequencing (LNS). Verbal learning and memory assessed by Hopkins Verbal Learning Test - Revised (HVLT-R) include scores for HVLT Recall, HVLT Retention and HVLT Discrimination Recognition. Processing speed and attention was assessed by Symbol Digit Modalities Test (SDMT). Visuospatial function was assessed by Benton Judgment of Line Orientation. Olfactory function was tested using University of Pennsylvania Smell Identification Test (UPSIT). Autonomic function was tested using Scales for Outcomes in Parkinson’s Disease - Autonomic Dysfunction (SCOPA-AUT). SCOPA-AUT questionnaire include assessment of gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, skin, respiratory, and sexual function.

Gastrointestinal symptoms were assessed by sum of items 5–7 of SCOPA-AUT questionnaire, which includes questions on frequency of bowel movement and constipation, as described previously [25]. Scores for constipation were also obtained from MDS-UPDRS Part I item 1.1 as described previously [26].

Although it is hypothesized that hyperhidrosis is more prevalent in late stage PD and with higher dose of Levodopa medication [6], we included thermoregulatory function in our analyses of early drug-naïve PD participants. In the SCOPA-AUT questionnaire, items 17–18 and 20–21 assess perspiration and temperature sensitivity respectively and sum of these items was used to define thermoregulatory variable.

2.6. Assessment of cerebrospinal fluid (CSF) biomarkers

CSF biomarkers measured in the PPMI include total unphosphorylated α-synuclein, total tau (T-tau), tau phosphorylated at Thr181(P-tau) and amyloid beta1–42 (Aβ1–42). CSF samples for PPMI were obtained by lumbar puncture. CSF and blood collection and analysis of CSF and serum biomarkers in the PPMI have been described previously [24,27].

Details on sample handling, shipment and storage are available in the PPMI biologics manual at ppmi-info.org. As described previously in the PPMI [24,27], CSF Aβ1–42, T-tau and P-tau were analyzed using xMAP-Luminex technology and INNO-BIA AlzBio3 immunoassay (Fujirebio-Innogenetics, Ghent, Belgium). CSF α-synuclein and CSF hemoglobin levels were analyzed using commercial immunoassay kits (BioLegend; formerly Covance).

Details of test scores and test direction are included in Supplementary Document 1.

2.7. Statistical analyses

Skin Conditions and PD risk.

Statistical analyses were performed using R version 3.5.1. We examined the association between presence of any skin condition, as well as individual skin conditions and PD using logistic regression with PD as the binary dependent outcome adjusted for age in years, sex (female/male), education years (binary <13 years or ≥ 13 years of education) and NSAID use (binary, no NSAID use or NSAID use).

Predictors of Skin Conditions in PD.

Among participants with PD, we used logistic regression with ‘any skin condition’ as the binary dependent outcome adjusted for age, sex, education years, NSAID use and PD duration to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between demographic variables, motor scores, non-motor scores and biomarker measures and presence of any skin condition. For continuous scores, we scaled factors by interquartile range (IQR), using the ‘IQR’ function in R. Therefore, the reported OR in these analyses reflects per-interquartile range increase.

Sensitivity Analyses.

Prior studies have observed changes in CSF α-synuclein level due to contaminating blood products attributed to leakage of hemoglobin (Hb) during lumbar puncture, as described previously [27]. We therefore conducted sensitivity analyses for CSF α-synuclein, excluding participants with CSF Hb concentration>=200 ng/ml, to avoid potential impact of Hb contamination on CSF α-synuclein level.

We used Bonferroni correction to account for multiple comparisons.

3. Results

3.1. PD participants versus healthy controls

The mean age of PD participants was 61.7 years (SD: ± 9.71 years) and mean disease duration was 6.77 months (SD: ± 6.79 months). The mean age of HC was 60.9 years (SD: ± 11.2 years), 95% of PD participants and 94% of HC identified as white. 41% of participants with PD (N = 175) and 32% of HC (N = 63) reported any skin condition. 4% (N = 23) reported more than one skin condition. Of the participants who reported multiple skin conditions, 1 HC reported three skin conditions while 5 HC and 17 PD participants reported two skin conditions.

Among 423 PD participants and 196 HC included in this study, the most common skin conditions reported were basal cell carcinoma (11% PD; 6% HC), eczema (4% PD; 4% HC), melanoma (4% PD; 2% HC), psoriasis (3% PD; 2% HC), rosacea (3% PD; 5% HC), squamous cell carcinoma (2% PD; 2% HC) and seborrheic skin conditions (2% PD; 2% HC). Other skin conditions included acne, actinic keratosis, dermatitis, benign cysts and skin growth, dry skin, herpes, sun spots etc. (17% PD; 15% HC) (Table 2).

Table 2.

Association between skin conditions and odds of having PD.

	PD	HC	Adjusted ORsd (95% CI)	Multivariate p
	n = 423	n = 196
Skin Conditions a
No Skin Condition	248 (59%)	133 (68%)	REF
Any Skin Condition	175 (41%)	63 (32%)	1.49 (1.04–2.16)	0.03b, f
Basal Cell Carcinoma	47 (11%)	11 (6%)	2.05 (1.02–4.08)	0.04b, f
Melanoma	16 (4%)	3 (2%)	2.32 (0.66–8.14)	0.19
Squamous Cell Carcinoma	9 (2%)	3 (2%)	1.26 (0.34–4.73)	0.73
Eczema	17 (4%)	7 (4%)	1.17 (0.47–2.91)	0.73
Psoriasis	13 (3%)	4 (2%)	1.39 (0.44–4.35)	0.57
Rosacea c	13 (3%)	9 (5%)	0.66 (0.27–1.58)	0.35
Seborrheic Skin Conditions g	7 (2%)	3 (2%)	1.35 (0.32–5.59)	0.68
Other Skin Conditions e	70 (17%)	30 (15%)	1.14 (0.71–1.85)	0.59

^an (%).

^bp < 0.05.

^fBonferroni adjusted p > 0.99.

^gAdjusted for scaled age, sex, education years and NSAID use.

^cRosacea included acne rosacea and ocular rosacea.

^dSeborrheic included seborrhea, seborrheic dermatitis and seborrheic keratosis.

^eOther, common skin conditions less than cutoff prevalence of 1.6% include: actinic keratosis, atopic dermatitis, benign cysts and skin growth, dermatitis, dry skin, herpes, sunspots etc. (other skin condition is a subset of any skin condition).There are overlaps in skin conditions.

We observed an association between presence of any skin condition and PD after adjusting for age, sex, education years and NSAID use (OR = 1.49, 95% CI = 1.04–2.16). In analyses focused on individual skin conditions, we observed an association between basal cell carcinoma and PD, after adjusting for the above covariates (OR = 2.05, 95% CI = 1.02–4.08). None of the other skin conditions were associated with PD (Table 2). Furthermore, the associations between any skin condition or basal cell carcinoma and PD were no longer significant after Bonferroni correction for multiple comparisons.

3.2. Baseline demographics of PD participants with and without skin conditions

Among 423 PD participants, 175 reported any skin condition. The mean age of PD participants with skin conditions was 63.3 years (SD: ± 9.21 years) and PD participants without skin conditions was 60.5 years (SD: ± 9.91 years) (Table 1).

Table 1.

Participant demographics.

	PD			HC
	All	With Skin Condition	Without Skin Condition
	n = 423	n = 175	n = 248	n = 196
Age, yearsb	61.69 ± 9.71	63.31 ± 9.21	60.54 ± 9.91	60.84 ± 11.23
Minimum, Maximum	33.52, 84.89	34.86, 84.89	33.52, 80.22	30.60, 83.70
Malea	277 (65%)	112 (64%)	165 (67%)	126 (64%)
Race (Caucasian)a	403 (95%)	169 (96%)	234 (94%)	185 (94%)
<13 years	76 (18%)	25 (14%)	51 (21%)	29 (15%)
≥ 13 years	347 (82%)	150 (86%)	197 (79%)	167 (85%)
PD Duration, monthsb	6.77 ± 6.79	6.48 ± 6.83	6.80 ± 6.44	-
Minimum, Maximum	0, 36.50	0.93, 35.50	0, 36.5
Family History of PDb, c
0	319	137 (78%)	182 (74%)	186
1 to 5	203	38 (22%)	65 (26%)	10
NSAID Use
0	401 (95%)	164 (94%)	237 (96%)	169 (86%)
1	16 (4%)	9 (5%)	7 (3%)	20 (10%)
NA	6 (1%)	2 (1%)	4 (2%)	7 (4%)

Participant demographics at screening visit.

^an(%).

^bMean ± SD.

^c1 PD subject is missing family history.

Among participants with PD, higher age (OR = 1.68, 95% CI =1.21–2.35, per IQR of 15.7 units increase in age) and education (OR =1.70, 95% CI =0.99–2.91, binary <13 years or ≥ 13 years of education), were associated with increased odds of having a skin condition, after adjustment for covariates. In these participants, we did not observe any association, in multivariate logistic regression analyses, between sex, race, family history of PD, NSAID use or PD duration and risk of having a skin condition. After Bonferroni correction, none of the above associations retained statistical significance.

3.3. Baseline PD severity, motor and non-motor assessments of PD participants with and without skin conditions

Among participants with PD, the odds of any skin condition was not associated with MDS UPDRS Parts I, II, III and total scores, Hoehn and Yahr stage, RBD, ESS, GDS, STAI, MoCA or LNS. In multivariate analyses, better executive function and working memory, as assessed by SFT total scores (OR = 1.45, 95% CI = 1.07–1.96, per IQR of 16 units increase in SFT), as well as better verbal learning and memory, as assessed by HVLT retention scores (OR = 1.55, 95% CI = 1.09–2.22, per IQR of 0.3 units increase in HVLT retention scores) were associated with increased odds of having any skin condition among participants with PD, after adjustment for age, education years, sex, NSAID use and PD duration. However, these associations were no longer significant after Bonferroni correction for multiple comparisons. None of the other non-motor scores considered were associated with presence of skin conditions. These results are presented in Fig. 1 and Supplementary Table 1.

Fig. 1.

Association between any skin condition and predictors among PD participants.

3.4. Baseline CSF measures of PD participants with and without skin conditions

We did not observe any association between CSF α-synuclein test values, CSF P-tau, T-tau, Aβ1–42 and T-tau/Aβ1–42 ratio and odds of any skin condition among participants with PD. Results of sensitivity analyses excluding participants with CSF hemoglobin levels >=200 ng/ml (Supplementary Table 2) did not differ substantially from those of our primary analyses (Fig. 1 and Supplementary Table 2).

4. Discussion

In this study, we examined the association between prevalence of skin conditions and PD in the PPMI cohort, and characteristics of PD participants with versus without skin conditions. We observed an association between presence of skin conditions overall, as well as basal cell carcinoma specifically and PD. We also observed somewhat better cognitive function among PD participants with skin conditions compared to those without. However, none of the associations were significant after applying the Bonferroni correction for multiple comparisons.

Although the etiopathology of each skin condition is different, common mechanisms between PD and skin conditions include melanin and neuromelanin pathways, α-synuclein pathology, inflammation and common genetic mechanisms [7,21,28]. Inflammation may be a shared mechanism contributing to both PD and inflammatory skin conditions [12]. Matrix metalloproteinases (MMPs), implicated in PD pathology, are also associated with rosacea. Increase in MMPs, including MMP-3 and MMP-9, are reported in the skin of rosacea patients, contributing to inflammation induced extracellular matrix and tissue damage [12]. Chronic peripheral inflammation observed in inflammatory skin conditions like eczema and psoriasis are also associated with PD [10]. Reducing inflammation using NSAIDs has been suggested to be protective in PD [1,10]. However, in our study, adjustment for NSAID use did not lead to substantially different results. Autonomic dysfunction is commonly reported in PD [21,22] and is associated with α-synuclein aggregation in sweat glands [13]. Studies have reported differences in sebum in PD participants compared to HC [15]. We examined measures of autonomic function in our study, including thermoregulatory and gastrointestinal symptoms. None of these autonomic function measures were different between PD participants with versus without skin conditions. Studies have also reported common genetic and immune mechanisms in skin cancers and PD [7,12,14]. Compared to HC, it is hypothesized that PD skin is more vulnerable to sun damage induced neoplastic skin lesions and skin cancer [17]. Pigmentation markers such as tyrosinase (TYR) and melanocortin-1 receptor (MC1R) are hypothesized as common mechanisms in PD and skin cancer [7,20]. MC1R gene variants are associated with skin and hair pigmentation. It is reported that individuals with MC1R Arg151Cys variant allele, specifically homozygous variant allele for light skin and red hair color, are at a higher risk for developing PD [1,7]. There may be other mechanisms associated with skin cancer and PD, since a recent study in a non-Caucasian population observed an increased risk of nonmelanoma skin cancer in female PD participants above 65 years of age, and an increased risk of melanoma in male PD participants above 65 years of age compared to the general population [20]. Family history of melanoma is reported to increase PD risk [7]. Leucine rich repeat kinase 2 (LRRK2) G2019S mutation in PD is hypothesized to increase risk for certain cancers, including skin cancer [14]. The Rochester Epidemiology Project has reported an increased risk of nonmelanoma skin cancer in PD cases compared to controls and implicate melanin dysfunction and sun exposure as common causal mechanisms [18]. Transcriptome analyses of PD skin punch biopsies show downregulation of over 80% genes involved in dermal and epidermal homeostasis in PD skin compared to HC skin. The study hypothesized that dysregulation in skin homeostasis increases vulnerability to environmental and mutagenic factors leading to chronic dysregulation and predisposition to skin cancer in PD compared to HC [28].

Cognitive impairment is a well-documented non-motor comorbidity in PD [5,27]. Approximately 50–80% of PD patients go on to experience PD dementia (PDD), or other forms of cognitive decline over the course of their illness, particularly with advancing age [5]. We examined whether the presence of skin condition was associated with cognitive performance in PD, and observed that PD participants with skin conditions had higher cognitive scores in the domains of executive function, working memory and verbal learning based on SFT total scores and HVLT retention scores, after adjusting for age, education years, sex, PD duration and NSAID use. These analyses, however, were no longer significant after adjustment for multiple comparisons. Several other tests, including LNS, HVLT recall, HVLT discrimination recognition and SDMT, while not statistically significant, tended towards a positive association with presence of skin condition. It is hypothesized that deficits in semantic fluency and delayed recall and retention in the HVLT indicate dysfunction in cortical brain regions in early PD, while deficits in other domains such as visuospatial function are observed in later stages of PD (Supplementary Document 1). Interestingly, nonmelanoma skin cancer, the most common type of skin cancer, was associated with better cognitive function and reduced risk of Alzheimer’s disease in the Einstein Aging Study, a longitudinal community-based investigation of older adults in New York City [29]. This report of better cognitive function among those with skin cancer are in agreement with our study, and suggests that skin health may serve as a marker of one of more factors that are involved in cognitive decline among PD patients. One such factor could be education, which is strongly correlated with cognitive function and could lead to better access to medical care (and thus a higher probability of receiving a skin condition diagnosis). In our study, PD participants who reported skin conditions were more educated and older compared to those without skin conditions. However, adjustment for education (as well as age) did not substantially impact our results, and we observed associations between skin condition and SFT total scores and HVLT retention scores (prior to multiple comparisons correction), after adjusting for education. Previous studies have attributed shorter education years to poorer verbal learning scores [30]. We did not have measures to assess medical care in our study and were thus unable to adjust for this potential source of confounding. Other confounding variables include physical activity, which is protective against cognitive decline, but could contribute to increased risk for skin cancer due to sun exposure, ultraviolet radiation and flareups of other skin conditions [28], as well as personality, psychosocial and socioeconomic variables [29].

To examine potential biological reasons for this association and to corroborate our findings regarding differences in cognitive test performance, we compared levels of CSF biomarkers relevant to cognitive function [30] among PD participants with versus without skin conditions. Lower CSF Aβ42 and T-tau are reported in PD compared to HC [27]. CSF Aβ38, 40, 42, T-tau, P-tau181 and T-tau/Aβ1–42 ratio is utilized to measure changes in PDD. It is proposed that simultaneous measurements of CSF biomarkers Aβ1–42, T-tau, P-tau181, and α-synuclein, may provide diagnostic value, biological insight for disease progression and reflect heterogeneity in clinical features in early PD [27]. Some studies report lower levels of P-tau181 in PD [27] and others report higher levels of P-tau associated with decreased executive function [30]. Studies have reported lower levels of CSF Aβ42 associated with decreased verbal and phonetic fluency scores [30]. In early PD, lower CSF Aβ1–42 indicate amyloid plaques and Aβ pathology and is associated with deficits in memory and executive function [30]. Likewise, studies have reported an association between total α-synuclein and phonetic fluency in PD [30]. Therefore, we analyzed association of CSF α-synuclein, Aβ1–42, T-tau, P-tau and T-tau/Aβ1–42 ratio between PD participants with versus without skin conditions. Despite having observed better performance on cognitive tests such as SFT total scores and HVLT retention scores among PD with skin conditions, we did not see corresponding differences between the two groups in the relevant CSF biomarkers assessed in this study, potentially, suggesting that differences in education, medical care access or other factors are more likely or that other biological mechanisms such as DNA methylation (associated with skin cancer and AD) [29], may explain better cognition in PD participants with skin conditions. Larger, better powered studies are needed to explore whether the observed differences in cognitive function, in the absence of motor and other PD-specific differences between PD participants with and without skin conditions, is due to confounding or has potential biological underpinnings.

Some investigators have proposed a potential diagnostic utility of skin conditions and cutaneous α-synuclein deposition in PD [21]. Cervical cutaneous denervation is associated with increased dermal localization of pathological α-synuclein species, and measuring cervical cutaneous denervation as a potential biomarker for PD progression is proposed [13]. Studies have also reported significantly high phosphorylated α-synuclein in dermal nerves of PD cases compared to HC, and have observed peripheral neurodegeneration in PD skin biopsies [19]. Since α-synuclein aggregation is detected in peripheral nerve fibers and pathological changes associated with PD manifest systemically [13,19,28], skin biopsies are proposed as predictive and diagnostic tools to measure PD relevant pathological changes [19,21, 28]. It is hypothesized that altered skin microflora in PD is associated with differences in sebum metabolites, and it is proposed that volatile sebum metabolites in the skin could be utilized as a potential biomarker for early detection of PD [15].

PD is a heterogenous disorder, with heterogeneity largely defined on the basis of clinical characteristics [27]. In this study, we considered a number of clinical variables relevant to skin health, PD heterogeneity and severity. To examine whether PD participants with skin conditions had a more severe PD phenotype, we measured differences in MDS-UPDRS scores and Hoehn and Yahr staging and observed no significant differences in severity between PD participants with versus without skin conditions. Certain skin conditions, like hyperhidrosis and seborrhea, are associated with autonomic dysfunction [6,22]. Therefore, we measured differences in autonomic scores, including thermoregulatory function, between PD participants with versus without skin conditions, and observed no significant differences. We also assessed non-motor scores including sleep disorder and olfactory dysfunction [4], anxiety, depression and constipation scores, and observed no significant differences. Overall, these findings suggest that skin health may have limited utility in distinguishing between PD subtypes at baseline, utilizing the PPMI drug-naïve early PD cohort.

Strengths of our study include a large cohort of early drug-naïve PD participants and assessment of PD-relevant motor, non-motor and biomarker measures [23]. PPMI is one of the largest prospective longitudinal study for validating PD progression biomarkers. Since we focus on early drug-naïve and untreated PD participants, our study results are not likely confounded by PD medication use.

An important limitation of our study is that skin conditions were self- reported and not collected systematically; there were no standardized protocols and medical record verifications for skin conditions in the PPMI. Study limitations also include a cross-sectional analysis focused on initial screening and baseline PPMI assessments. Since our study is cross-sectional, causality cannot be ascertained. Longitudinal studies are needed to examine if skin conditions are associated prospectively with increased risk of PD as well as PD severity and progression. Limited samples size, especially in subgroup analyses comparing PD cases with and without skin conditions, is also a limitation of our analyses. The PPMI cohort is predominantly Caucasian (>94%) and since lighter skin is hypothesized to be more vulnerable to sun induced damage and increased risk of skin cancer [7], the results of our study, with regard to association between basal cell carcinoma and PD, may not generalizable to other, more racially diverse population. Due to lack of relevant data, we did not control for sun exposure and tobacco use in our analyses and cannot rule out potential confounding by these factors. Furthermore, as discussed above, we were not able to fully control for a number of important covariates, including smoking, socioeconomic status and healthcare access, which is an important limitation of our study.

In summary, in our cross-sectional study using the PPMI dataset, we observed that participants with any skin condition as well as those with basal cell carcinoma had higher odds of early drug-naïve PD. PD participants with skin conditions were older and better educated, had higher executive function, verbal and working memory as measured by SFT total scores and HVLT retention scores, compared to PD participants without skin conditions. However, none of these associations were significant after Bonferroni correction for multiple comparisons and should thus be interpreted cautiously. Larger, prospective studies are needed to better address the association of skin conditions with PD severity and progression.