Common Benign Melanocytic and Non-Melanocytic Skin Tumors among the Elderly: Results of the Graz Study on Health and Aging

Abstract

Background and Objectives

Benign skin tumors are the most common skin findings and contribute to the major reasons for consulting a dermatologist. However, the frequency of benign skin tumors concerning different body areas and their relationship with sun-related behavior have not been sufficiently characterized. We aimed to improve knowledge about the anatomic distribution of the most frequently occurring benign skin tumors among a healthy predominant elderly population. Furthermore, we investigated associations with sun-related habits.

Methods

In total, 100 participants, 37 men, and 63 women (mean age: 67.2 years; range: 46–86 years) were enrolled in the Graz Study on Health and Aging (GSHA) cohort. Full body images were investigated for melanocytic nevi, seborrheic keratoses, hemangiomas, dermatofibromas, and lentigines. Information on the phenotypic trait, sun exposure, use of sun-protective measures, and history of sunburns was collected in a questionnaire.

Results

Common melanocytic nevi were the most frequently encountered skin lesions. Male sex was associated with multiple common nevi on the abdomen and the presence of atypical nevi. High sun exposure in central European latitudes during adolescence was positively associated with multiple common nevi on the total body. Multiple common nevi and atypical nevi on the back correlated with frequent use of sunscreens with SPF during young adulthood and adolescence, respectively.

Conclusion

Our study adds new knowledge about the most frequently occurring benign skin tumors, considering all visible body areas. This research may serve as a reference basis for following epidemiological studies.

Introduction

The elderly population, defined as people aged over 60 years, is constantly increasing and will raise from 12% to 22% between 2015 and 2050, following the World Health Organization prognosis [1, 2]. In Austria, nearly one-fourth of the overall population is part of this age category [3].

The process of aging is not only accompanied by alterations in cardiovascular, musculoskeletal, metabolic, and neuropsychiatric systems, but also by a variety of skin changes [4, 5]. It is known that the number of systemic diseases correlates with the number of different skin disorders, including benign skin tumors [6]. For this reason, various healthcare professionals, including dermatologists, will be increasingly faced with the management of age-related diseases.

Benign melanocytic and non-melanocytic skin tumors are one of the most frequently encountered skin findings [6, 7]. Besides actinic keratoses and nonmelanoma skin cancer, seborrheic keratoses, melanocytic nevi, solar lentigines, and other benign skin neoplasms represent the most common reasons for seeking care in public or private healthcare settings in the Spanish population [8]. Considering this fact, these skin findings seem to cause remarkable uncertainty and discomfort among patients, despite their benign nature.

To date, studies among the elderly population have mainly focused on the prevalence of common dermatologic diseases, reaching from dermatitis, infections, and pruritus to premalignant and malignant tumors [9, 10, 11, 12]. To our knowledge, the prevalence of benign skin tumors among the elderly has been primarily investigated considering special body sites like face, head, and neck regions [7, 13]. In fact, data concerning benign skin tumors, their site-specific occurrence, and relationship with sun-related habits in this special age group are still lacking.

Patients and Methods

Study Design

We performed a descriptive cross-sectional study to investigate the anatomic distribution of benign melanocytic and non-melanocytic skin tumors as well as possible associations to sun-related behavior.

Recruitment of Participants

The Graz Study on Health & Aging (GSHA) is a population-based study, which aims to identify core processes of aging and subsequently generate high-impact targets for the prevention and therapy of age-associated diseases. The total sample of the initial pilot phase of the interdisciplinary GSHA was 100 participants. All participants were referred for dermatological full body examination at the Department of Dermatology, Medical University of Graz, Austria. Inclusion criteria for the GSHA were the age of at least 45 years and primary residence in Graz. Participants suffering from malignant diseases within the last 2 years were excluded from the study.

Data Collection

Full body images were captured using the Automated Total Body Mapping® (ATBM®) technology provided by the company FotoFinder® (Bad Birnbach, Germany). Per person, 20 high-resolution digital photographs in RAW image format were automatically created by a reflex camera in combination with a polarized flashlight from different body positions. The digital photographs were supplemented with dermatoscopic pictures using the FotoFinder Medicam 800HD, an integrated full HD video camera with optical live zoom, in case of skin lesions measuring at least 5 mm in diameter. To avoid unnecessary discomfort for the participants and extensive time consumption, dermatoscopic imaging of lesions smaller than 5 mm in diameter was not performed. The ATBM® technology displays an optimal tool for the evaluation of skin lesions, as it photographically covers up to 85% of the skin surface.

Full body images were clinically investigated by two of the investigators (V. Gruber and R. Hofmann-Wellenhof) for melanocytic nevi, seborrheic keratoses, hemangiomas, dermatofibromas, and lentigines, considering all visible skin areas − except scalp and genital area. Melanocytic nevi were further divided into common nevi, dermal nevi, atypical nevi, and congenital nevi, based on the criteria for clinical diagnosis published by Garbe et al. [14]. Criteria were slightly modified in our study, as we distinguished between common (flat) nevi and dermal (papillomatous) nevi. Furthermore, a diameter of at least 10 mm was not obligatory for the clinical diagnosis of a congenital nevus in our study. Pigmented lesions characterized by a diameter of at least 2 mm, well-defined border, regular margin, uniformly light to dark brown color, and a flat surface were diagnosed as common nevi. Elevated lesions showing a papillomatous surface and shades of brown to skin color as well as regular margins were defined as dermal nevi. The presence of at least three of the following features led to the clinical diagnosis of an atypical nevus: diameter of at least 5 mm, ill-defined border, irregular margin, different shades of brown within the lesion, or papular and macular components. The clinical diagnosis of a congenital nevus was established when a pigmented lesion exhibited at least three of the following criteria: well-defined border, regular margin, uniformly dark brown to black shades, papular or papillomatous surface, or hypertrichosis. Benign lesions were mainly diagnosed on macroscopic appearance. Seborrheic keratoses were defined as well-demarcated, round, or oval lesions with a stuck-on appearance, ranging from skin-colored to brown or black. Hemangiomas were round bright red macules or papules up to 5 mm in diameter. The clinical diagnosis of a dermatofibroma was made for pink to light brown-colored lesions with a size of five to 10 mm in diameter that show a central white patch surrounded by a delicate brown pigment network. Lentigines were defined as tan to dark brown macules with sharp demarcated irregular borders (“moth-eaten borders”).

The lesion site was assigned to one of seven defined body areas: face-neck, upper extremities, ventral thorax, upper back, abdomen, lower back-gluteal, and lower extremities. Site-specific frequencies were assessed by seven categories being defined by a lower and upper threshold frequency (0 lesions, 1–4 lesions, 5–9 lesions, 10–19 lesions, 20–49 lesions, 50–99 lesions, and 100 or more lesions).

Information on the phenotypic trait, sun exposure, use of sun-protective measures, and history of sunburns was collected using a questionnaire (see suppl. material). We considered different periods of life, which were defined as follows: adolescence (10–19 years), young adulthood (20–39 years), midlife (40–59 years), in the last year, and after the age of 60 years. Fitzpatrick skin types were assessed by the self-reported degree of skin erythema and skin pigmentation after sun exposure [15].

Statistical Evaluation

For the description of continuous variables, mean values and standard deviations (SDs) were calculated, after testing for data distribution. To identify gender-related differences regarding the anatomic distribution of benign skin lesions as well as their associations to specific sun-related habits, Fisher's exact test was used. Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were determined. A level of significance of 0.01 was set throughout the analysis. Statistical analysis was conducted using IBM SPSS Statistics 26 [International Business Machines Corporation, Armonk, NY, USA].

To obtain an estimation of the total body frequency of each skin tumor entity, the recorded lower limit of the seven categories (0 lesions, 1–4 lesions, 5–9 lesions, 10–19 lesions, 20–49 lesions, 50–99 lesions, and 100 or more lesions) was summed up for the seven body areas. Considering the variability of site-specific and total body frequencies depending on the type of skin tumor, we conducted a dichotomization for further statistical analysis (shown in Table 1). In the case of common nevi, 10 or more common nevi per body site and 20 or more common nevi on the total body were assumed as “multiple” common nevi.

Table 1.

Threshold values for site-specific and total body frequencies depending on the type of skin tumor

Type of skin tumor	Site-specific frequency	Total body frequency
Common nevus	<10 versus ≥10	<20 versus ≥20
Dermal nevus	0 versus ≥1	0 versus ≥1
Atypical nevus	0 versus ≥1	0 versus ≥1
Congenital nevus	0 versus ≥1	0 versus ≥1
Seborrheic keratosis	0 versus ≥1	<10 versus ≥10
Hemangioma	0 versus ≥1	<10 versus ≥10
Dermatofibroma	0 versus ≥1	0 versus ≥1
Lentigo	<5 versus ≥5	<20 versus ≥20

Results

Patient Characteristics, Phenotypic Traits, and Sun-Related Behavior

Between April 2016 and July 2017, 100 participants (37 men and 63 women) who met the above-mentioned inclusion criteria were examined. Participants were aged between 46 and 86 years with a mean age of 68.2 years (SD = 9.55 years) in men and 66.6 years (SD = 9.63 years) in women. Two-thirds of participants belonged to the age group of 60 years or older. No gender-specific differences regarding phenotypic traits were identified (shown in Table 2). Sun-related habits in men did not differ significantly from those in women (shown in online suppl. Table 1; for all online suppl. material, see www.karger.com/doi/10.1159/000529219).

Table 2.

Gender-specific data on phenotypic traits

	Men		Women		p value
	N	(%)	N	(%)
Fitzpatrick skin type
I	3	(8.1)	7	(11.1)	0.950
II	10	(27.0)	19	(30.2)
III	20	(54.1)	31	(49.2)
IV	4	(10.8)	6	(9.5)
Natural hair color at the age of 20 years
Dark brown	18	(48.6)	24	(38.1)	0.797
Light brown	8	(21.6)	19	(30.2)
Blonde	10	(27.0)	16	(25.4)
Black	1	(2.7)	3	(4.8)
Red	0	(0.0)	1	(1.6)
Eye color
Blue	11	(29.7)	19	(30.2)	0.820
Brown	12	(32.4)	18	(28.6)
Green	6	(16.2)	15	(23.8)
Gray	8	(21.6)	11	(17.5)
Natural skin color on sun-protected areas
Light	16	(43.2)	28	(44.4)	0.761
Intermediate	17	(45.9)	33	(52.4)
Dark	2	(5.4)	2	(3.2)
Descent
European	36	(97.3)	63	(100.0)	0.370
Asian	1	(2.7)	0	(0.0)
Facial ephelides at the end of summer at the age of 20 years
None/few	36	(97.3)	53	(84.1)	0.012
Various/many	0	(0.0)	10	(15.9)
Moles on the skin at the age of 20 years
None/few	28	(75.7)	48	(76.2)	1.000
Various/many	9	(24.3)	15	(23.8)

Absolute numbers, percentages in brackets, p value (Fisher's exact).

Melanocytic and Non-Melanocytic Skin Tumors

In 18 men (48.6%) and 24 women (38.1%), 20 or more common nevi were present on the total body. Multiple (≥10) common nevi were most frequently observed on the lower extremities in both men and women (10/37; 27.0% and 24/63; 38.1%, respectively). Male sex was associated with multiple common nevi on the abdomen (p < 0.001). High sun exposure in central European latitudes during adolescence was positively associated with multiple common nevi on the total body (OR = 9.33, 95% CI: 2.75–31.73, p < 0.001) and on the lower extremities (OR = 18.21, 95% CI: 4.65–71.32, p < 0.001) in women (shown in Table 3). In addition, the presence of multiple common nevi on the upper back in men correlated with frequent use of sunscreens with SPF during young adulthood (OR = 12.67, 95% CI: 2.00–80.14, p = 0.007) (shown in Table 4).

Table 3.

Significant associations between presence/absence of skin tumors and sun-related behavior in women

Type of skin tumor and corresponding anatomic region	Sun-related behavior	OR [95% CI]	p value
Presence of multiple common nevi
Total body (≥20)	High sun exposure in central European latitudes during adolescence	9.33 [2.75–31.73]	<0.001
Lower extremities (≥10)	High sun exposure in central European latitudes during adolescence	18.21 [4.65–71.32]	<0.001
Absence of atypical nevi
Lower back-gluteal	Low sun exposure in central European latitudes during midlife	1.54 [1.28–1.85]	0.002
Lower back-gluteal	Low sun exposure in southern regions during adolescence	49.00 [5.38–446.28]	<0.001
Absence of seborrheic keratoses
Upper back	Spending few hours on workdays partially sun-exposed in summertime during midlife	N/A	0.006
Absence of hemangiomas
Upper extremities	Spending many hours on the weekend partially sun-exposed in summertime during adolescence	0.18 [0.05–0.58]	0.004
Abdomen	Spending many hours on the weekend partially sun-exposed in summertime during adolescence	0.12 [0.03–0.61]	0.008
Presence of ≥1 hemangioma
Upper extremities	Spending few hours on workdays partially sun-exposed in summertime during the last year	0.14 [0.03–0.70]	0.009

Odds ratio (OR), 95% confidence interval [95% CI], and p value (Fisher's exact). N/A, not applicable.

Table 4.

Significant associations between presence/absence of skin tumors and sun-related behavior in men

Type of skin tumor and corresponding anatomic region	Sun-related behavior	OR [95% CI]	p value
Presence of multiple common nevi
Upper back	Frequent use of sunscreen with SPF during young adulthood	12.67 [2.00–80.14]	0.007
Presence of ≥1 atypical nevus
Lower back-gluteal	Frequent use of sunscreen with SPF during adolescence	23.00 [2.48–213.70]	0.006
Presence of ≥5 lentigines
Lower extremities	Rare use of sunscreen with SPF during adolescence	1.75 [1.11–2.76]	0.004

Odds ratio (OR), 95% confidence interval [95% CI], and p value (Fisher's exact).

In 23 men (62.2%) and 40 women (63.5%), at least one dermal nevus was observed on the total body. Dermal nevi most frequently occurred on the upper back in men (9/37; 24.3%) and on the face-neck area in women (16/63; 25.4%).

The presence of at least one atypical nevus on the total body was more frequently observed in men than in women (19/37; 51.4% vs. 16/63; 25.4%; OR = 3.10, 95% CI: 1.31–7.32, p = 0.010). Atypical nevi primarily occurred on the abdomen in men (7/37; 18.9%) and on the upper back in women (8/63; 12.7%). Absence of atypical nevi on the lower back-gluteal region in women was positively associated with low sun exposure in central European latitudes during midlife (OR = 1.54, 95% CI: 1.28–1.85, p = 0.002) and low sun exposure in southern regions during adolescence (OR = 49.00, 95% CI: 5.38–446.28, p < 0.001) (shown in Table 3). Presence of atypical nevi on the lower back-gluteal region in men correlated directly with frequent use of sunscreen with SPF during adolescence (OR = 23.00, 95% CI: 2.48–213.70, p = 0.006) (shown in Table 4).

Congenital nevi were encountered in 6 men (16.2%) and 6 women (9.5%). They most frequently occurred on the upper extremities in men (4/37; 10.8%) and on the lower extremities in women (3/63; 4.8%).

Seborrheic keratoses occurred in 37 men (100.0%) and 59 women (94.0%). In 22 men (59.5%) and 39 women (61.9%), 10 or more seborrheic keratoses were present on the total body. They most frequently occurred on the ventral thorax in both male and female participants (29/37; 78.4% and 54/63; 85.7%, respectively). Absence of seborrheic keratoses on the upper back correlated with spending few hours on workdays partially sun-exposed in the summertime during midlife in women (p = 0.006) (shown in Table 3).

Hemangiomas occurred in 36 men (97.3%) and 56 women (88.9%). In 20 men (54.1%) and 25 women (39.7%), 10 or more hemangiomas were present on the total body. In both men and women, hemangiomas were most frequently observed on the ventral thorax (34/37; 91.9% and 52/63; 82.5%, respectively). Within female participants, spending many hours on the weekend partially sun-exposed in the summertime during adolescence was associated with lacking hemangiomas on the upper extremities (OR = 0.18, 95% CI: 0.05–0.58, p = 0.004) and abdomen (OR = 0.12, 95% CI: 0.03–0.61, p = 0.008) (shown in Table 3). Spending few hours on workdays partially sun-exposed in the summertime during the last year was associated with the occurrence of hemangiomas on the upper extremities in women (OR = 0.14, 95% CI: 0.03–0.70, p = 0.009) (shown in Table 3).

Dermatofibromas were present in 17 men (45.9%) and 24 women (38.1%). They primarily occurred on the lower extremities in both men and women (16/37; 43.2% and 17/63; 27.0%, respectively).

Lentigines were encountered in 37 men (100.0%) and 61 women (96.8%). In 25 men (67.6%) and 44 women (69.8%), 20 or more lentigines were present on the total body. In both men and women, lentigines primarily occurred on the upper extremities (35/37; 94.6% and 58/63; 92.1%, respectively). In male participants, the presence of five or more lentigines on the lower extremities correlated with the rare use of sunscreen with SPF during adolescence (OR = 1.75, 95% CI: 1.11–2.76, p = 0.004) (shown in Table 4). Statistically significant differences in gender-related distribution were only found for common nevi and atypical nevi (online suppl. Table 2).

Discussion

Our explorative study adds new knowledge about the anatomic distribution of the most frequently occurring benign skin tumors. Furthermore, we describe their relationship to sun-related behavior among a healthy predominant elderly cohort consisting of 100 participants.

We identified tumor- and gender-specific differences in anatomic distribution, which are largely in concordance with results from previous studies. We strengthened the observation that male sex is associated with multiple common nevi on the trunk and increased occurrence of atypical nevi [14, 16, 17, 18]. The reported predilection sites for all considered subsets of melanocytic nevi, lentigines, seborrheic keratoses, hemangiomas, and dermatofibromas are also in line with findings from prior research [11, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28]. One previous French study (PROOF study) [11], including 209 subjects with a mean age of 77.5 years, investigated the prevalence of benign skin tumors, considering simplified body areas (face, trunk, upper limbs, lower limbs). The reported prevalence of non-dermal nevi was 55%, which seems quite low in comparison with our results (all participants showed at least one common nevus on the total body). This discrepancy might be explained by the higher mean age of those participants and correspondingly lower nevus counts, as the number of these nevi constantly decreases with age, based on observations from cross-sectional studies [18, 29]. These findings were never confirmed by a large longitudinal study. However, we found substantial accordance for site-specific and total body prevalence for seborrheic keratoses, hemangiomas, and dermal nevi related to the PROOF study [11]. In contrast, the percentage of subjects revealing more than 50 lentigines, especially on the face and lower limbs, was much higher in the PROOF study compared to our findings (12% vs. 1%, 18% vs. 1%, respectively) [11]. Again, this difference could be explained by the older study cohort and the fact that the number of lentigines significantly increases with age [18]. Jayasinghe et al. [30] reported that males had the highest nevus counts on the trunk, as opposed to our findings (both men and women revealed multiple common nevi most frequently on the lower extremities). We considered both the entire thighs and lower legs as lower extremities, which might account for the greater nevus counts on this body area compared to the trunk.

Associations with sun-related behavior were identified for common nevi, atypical nevi, seborrheic keratoses, hemangiomas, and lentigines. High sun exposure in central European latitudes during adolescence correlated with multiple common nevi on the total body and the lower extremities in women. We substantiated the fact that adolescence constitutes a critical period for nevus development, whereby intermittent-high as well as chronic-moderate sun exposure is associated with high nevus counts [31, 32].

Frequent use of sunscreens was associated with multiple common nevi and the presence of atypical nevi on the back in men. The role of sunscreens in the development of nevi has been controversially discussed in the literature. One recent study from Italy reported higher nevus counts in children who applied sunscreen more than two times per day, compared to children who applied two times per day or less frequently. It is a known fact that the use of sunscreen frequently comes along with higher nevus counts due to prolonged sunbathing [17, 33]. Only the use of sunscreen with a SPF of 30 or more was associated with lower nevus counts [34]. Equal results were described by Iannacone et al. [35], who summarized the evidence from randomized controlled trials about the effects of sunscreen application on the incidence of various skin conditions, including melanocytic nevi. Herein, the use of a SPF 30 broad-spectrum sunscreen was characterized to attenuate the development of naevi in schoolchildren during an observation period of 3 years [36].

We observed a correlation between the absence of atypical nevi in the lower back-gluteal region and low sun exposure in southern regions during adolescence. Correspondingly, atypical nevi predominantly arise on the back after acute intensive sun exposure during childhood, for example, after a holiday in sunny climates [37].

Lacking seborrheic keratoses on the upper back in women was associated with spending a few hours partially sun-exposed in the summertime during midlife. Ultraviolet radiation has been identified as a risk factor for the development of seborrheic keratoses in several studies [22, 38], whereby UV-induced keratinocyte senescence seems to play a major role [39].

Absence of hemangiomas on the upper extremities and abdomen in women correlated with high sun exposure during adolescence. Until now, the etiologic role of ultraviolet radiation in the development of hemangiomas has been a poorly investigated issue. However, there is evidence for chronically UV-induced changes in skin angiogenesis such as reduction of cutaneous microvasculature and vessel obliteration [40], which might explain our finding.

In the case of lentigines, we observed an association between the rare use of sunscreens during adolescence and occurrence on the lower extremities in men. UV radiation, particularly the UVB spectrum (280–320 nm), is a well-established environmental risk factor for the development of lentigines [41].

Strengths and Limitations

Participants were examined following consistent inclusion and exclusion criteria. Some previous studies have mainly focused on particular body sites when reporting the prevalence of benign skin tumors. Within our study, we considered all visible skin regions and defined seven body areas to create a more detailed image of how benign skin tumors are anatomically distributed throughout the total body. When reporting the prevalence of common nevi, it should be noted that some results were not comparable between studies, as there is often disagreement on the definition of body areas.

We used the latest technologies to obtain multiple high-resolution digital photographs from different body positions and additional dermatoscopic pictures of skin lesions measuring five or more millimeters in diameter. These digital data strongly aided the accuracy of clinical diagnoses made.

For the assessment of sun-related habits, we used a standardized questionnaire. However, self-reported data concerning previous stages of life − for example, adolescence − might be limited in their validity due to recall bias. The diagnosis of benign skin tumors, which was based on clinical and − if available − dermoscopic features, was not confirmed histopathologically. Furthermore, we examined a limited number of individuals. Concomitantly, the reported prevalence of each skin tumor entity may not be representative for the general population.

In the questionnaire, participants were asked about the use of sun-protective measures and sun exposure. However, there was no question regarding the specific body sites that were exposed to and protected from the sun by clothing or by sunscreen, respectively.

Conclusion

Common melanocytic nevi were the most frequently occurring skin lesions. Multiple common nevi on the abdomen and the presence of atypical nevi were associated with the male sex. We observed an association between high sun exposure in central European latitudes during adolescence and multiple common nevi on the total body. Participants who frequently used sunscreens with SPF during young adulthood and adolescence were more likely to exhibit multiple common nevi and atypical nevi on the back. We aimed to display the variety of benign skin lesions among a predominantly elderly population. Various health care professionals and − in the first place − dermatologists will be more and more dealing with benign skin tumors in clinical routine. Therefore, supplying data regarding their prevalence and anatomic distribution as well as associations with sun-related behavior was a further motivation for our study. Moreover, our data can be used as a reference in following epidemiological studies regarding benign skin tumors and sun-related habits within populations from other geographic regions. This research contributes to the current knowledgebase, as we evaluated benign skin lesions not only on selected body sites but on the whole visible skin, using the latest technologies.

Key Message

We performed the first study that investigates common benign skin tumors of the visible skin and their associations with sun-related behavior among the elderly.

Statement of Ethics

The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. All subjects have given their written informed consent. All patient-related data were analyzed and reported anonymously. Ethical approval (approval number 26-573 ex 13/14) was granted within the framework of the Graz Study on Health & Aging (GSHA) by the Ethical Committee of the Medical University of Graz, Austria.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was supported in part by the City of Graz and the Austrian Ministry of Science under the aegis of the EU Joint Programme − Neurodegenerative Disease Research − www.jpnd.eu.

Author Contributions

Viktoria Gruber and Rainer Hofmann-Wellenhof had full access to all of the data in the study and were involved in the drafting of the manuscript. Viktoria Gruber took responsibility for the integrity of the data and the accuracy of the data analysis. Rainer Hofmann-Wellenhof and Peter Wolf were involved in the study concept and design and supervised the study. Viktoria Gruber, Rainer Hofmann-Wellenhof, and Peter Wolf were involved in the interpretation of data. Viktoria Gruber and Elena Lucia Hofmann-Wellenhof were involved in the acquisition of data. Peter Wolf, Helena Schmidt, Andrea Berghold, and Andreas Wedrich were involved in the critical revision of the manuscript for important intellectual content.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.

Supplementary Material

Supplementary data

Supplementary data

Funding Statement

This study was supported in part by the City of Graz and the Austrian Ministry of Science under the aegis of the EU Joint Programme − Neurodegenerative Disease Research − www.jpnd.eu.