The concept of the skin as a factor in Parkinson’s disease is not new, but several factors are just now coming together to force it onto the verge of clinical practice.
A precise diagnosis can be important from two perspectives. It can identify a condition which is treatable. It can also demarcate a contraindication, something that is not treatable. For example, many spa treatments can provoke an inflammatory reaction, so applying them to already inflamed skin is a recipe for disaster.
Indeed, science is long overdue to give skin the credit it deserves, both in its true size and significance in human health. In terms of size, skin surface area is accepted to be only 2 meters squared – basically a hide. However, a recent recalculation, expanding skin area to in excess of 25 meters squared, also boosts the developing role accorded to the skin microbiome.2
Only in this century has the gut transitioned from a mere conduit for food into the second brain – an enteric nervous system ranking alongside the central nervous system.3 One major feature is the gut microbiome, a collection of beneficial and harmful bacteria. This is paralleled by the skin microbiome and it appears that both microbiomes communicate, not just with one another, but also with the brain. Another common denominator is a protein, α-synuclein, which is genetically associated with Parkinson’s disease that is present not only in the central nervous system and the enteric nervous system, but also in the skin. This makes Parkinson’s disease one of a number of so-called synucleinopathies. Alpha-synuclein becomes pathogenic when it misfolds and becomes tangled, like dropping a ball of yarn or when playing with a yo-yo goes wrong.
Human skin, with its large surface, harbors a wide variety of microbes, which include bacteria, fungi, viruses, archaea and skin mites. 2,4-9 Malassezia are a major component of the skin microbiome. They occur as skin commensals, but are also associated with various skin disorders and bloodstream infections.10
Thus, the working field for an aesthetician has just been expanded by more than tenfold, from a small table to a 20-foot by 14-foot room. The difference derives, mostly, from unfolding follicles. Malassezia yeasts grow in these follicles and produce inflammation. It is also no longer just a hide, it is a living microbiome.
Their odd name derives from being named for Louis-Charles Malassez, a 19th century French scientist who first identified the yeasts in the outer layer of the epidermis of patients with seborrheic dermatitis.11 Seborrheic dermatitis may be defined as excessive secretion of oil by sebaceous glands, with seborrhea of the head, face, and neck. The highest density is found in the sebaceous (oily skin) areas, namely the scalp, face, and upper trunk.
In one of those remarkable examples of serendipity, a Scottish housewife, Joy Milne, has emerged, stunning the scientific community and grabbing headlines in the media by proving that she could smell Parkinson’s disease, even before it had been diagnosed. The smell seems to emanate from fungal infections attributed to the genus malassezia, particularly the scent remaining across the back from a worn T-shirt.
The association between the skin and Parkinson’s patients was recognized as early as 1927, when Krestin described a cutaneous manifestation of post-encephalic Parkinsonism as shiny and greasy, with characteristic scarring acne.12 The condition derived from the rampant flu pandemic of the period. Parkinson’s disease itself does not have a known cause; in medical jargon, it is idiopathic.
It must also be noted that systemic antibiotic treatment of acne (for example, minocycline) changes the composition and diversity of skin microbiota. A similar predicament is seen with the gut. Modern medicine, to date, has been quick to eradicate bacteria via the use of broad-spectrum antibiotics, but has been painfully slow in repopulating desirable bacteria, usually through the use of prebiotics, probiotics, and postbiotics, all of which are heavily promoted in the media.
Broxmeyer originated his spore hypothesis that Parkinson’s disease may be due to reactivation of spores, either fungal or bacterial, in the brain – perhaps involving some form of mold.13 Berstad updated this, although they chose endospores from an actinomycete as their most likely candidate.14
THE KEY PATHOGEN
Examples of the malassezia genus are part of normal human flora, however, they are also thought to exacerbate a number of skin conditions such as pityriasis (or tinea) versicolor, malassezia folliculitis, seborrheic dermatitis, atopic dermatitis, and even some life-threatening nosocomial bloodstream infections.1 Seborrhea may present on the face and scalp and appears as flaking skin with red patches underneath. Seborrhea tends to recur frequently and can be a source of acute embarrassment, an additional stressor that could further worsen the quality of life for the Parkinson’s patient.15 Malassezia globosa is emerging as the key pathogen in Parkinson’s disease patients with seborrheic dermatitis.
In order for the professional to make a differential diagnosis, tinea (pityriasis) versicolor, in this case, a number of possibilities need to be excluded such as erythrasma, hypopigmented mycosis fungoides, pityriasis rosea, post-inflammatory hypo- or hyperpigmentation, pityriasis alba, seborrheic dermatitis, and vitiligo.
As a second example, consider malassezia (pityrosporum) folliculitis an acneiform eruption consisting of chronic pruritic follicular papules and pustules on the upper trunk, neck, and upper arms. The differential diagnosis includes acne vulgaris, bacterial folliculitis, and eosinophilic folliculitis.
Seborrheic dermatitis is a common chronic inflammatory skin disorder affecting up to three percent of the general population. However, research at the University of Belgrade in Serbia by Dr. Valentina Arsic Arsenijevic has confirmed that it is far more frequent among those with Parkinson’s disease, reaching a prevalence as high as 59 percent.1 This twentyfold increase is intriguing and has led to seborrheic dermatitis being confirmed as a possible precursor to Parkinson’s disease.16 Professor Caroline Tanner of the University of California San Francisco has endorsed seborrheic dermatitis as a premotor feature of PD, which could serve as an early disease marker of PD.17
As numerous skin disorders, including melanoma, affect patients with Parkinson’s disease, awareness and correct treatments are important to improve and even save patients’ lives. Skin care professionals should re-emphasize the importance of sun protection, including limiting exposure and using high-factor sun blocking agents for them.18
Appropriate antifungal treatment, such as ketoconazole, can be useful for Parkinson’s disease patients by reducing malassezia growth and enzyme production.17 Also, when using oral ketoconazole, it is important for the patient to exercise to the point of sweating one hour after taking the medication, as it is delivered to the skin surface through sweat.
Anti-inflammatory agents in the form of topical steroids or topical calcineurin inhibitors can also be used in treatment, thus improving the patient’s well-being and quality of life.18
It has now become possible to select the treatment by testing its effectiveness in-vitro. In microbiology, the minimum inhibitory concentration is the lowest concentration of a chemical which prevents visible growth of a bacterium. Some malassezia species showed high minimum inhibitory concentration values for ketoconazole. The lowest minimum inhibitory concentrations were found for the azoles (itraconazole, posaconazole, and voriconazole). All malassezia species were resistant to echinocandins and griseofulvin.19
Thus, a simple skin sample can not only save a lot of time, in the precise selection of an effective drug regimen, neurodegenerative disorders, such as Parkinson’s disease, may shortly be diagnosed through investigation of the skin.18
This is also a reminder to not always jump to heavy duty drugs. Perhaps a shampoo will be effective. While seborrheic dermatitis is treatable with topical ointments and creams, dandruff shampoos (coal tar or selenium-based) are often effective if it is in the scalp or over the eyebrows and forehead; it is advised not to overuse them; their use should be restricted to no more than twice weekly.20
These are exciting times for those in the field of skin. It is no longer simply the outer layer we inhabit and decorate to present to the world but a vital component of our entire being.
1 Arsenijevic, V.S.A., D. Milobratovic, A.M. Barac, B. Vekic, J. Marinkovic, and V.S. Kostic. “A laboratory-based study on patients with Parkinson’s disease and seborrheic dermatitis: the presence and density of Malassezia yeasts, their different species and enzymes production.” BMC dermatology 14 (2014): 5.
2 Gallo, R.L. “Human skin is the largest epithelial surface for interaction with microbes.” Journal of Investigative Dermatology 137 (2017): 1,213–1,214.
3 Gershon, M.D. The Second Brain. Harper Collins, New York: 1998.
4 Findley, K., J. Oh, J. Yang, S. Conlan, C. Deming, J.A. Meyer, D. Schoenfeld, E. Nomicos, M. Park, H. Kong, et al. “Topographic diversity of fungal and bacterial communities in human skin.” Nature 498 (2013): 367–70.
5 Meyers, J.M. and K. Munger. “The viral etiology of skin cancer.” Journal of Investigative Dermatology 134 (2014): 29–32.
6 Hannigan, G.D., J.S. Meisel, A.S. Tyldsley, Q. Zheng, B.P. Hodkinson, A.J. Sanmiguel, S. Minot, F. Bushman, and E. Grice. “The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome.” mBio 6 (2015): 01578–01515.
7 Horz, H.P. “Archaeal lineages within the human microbiome: absent, rare or elusive?” Life 5 (2015): 1333–45.
8 Moissl-Eichinger, C., A.J. Probst, G. Birarda, A. Auerbach, K. Koskinen, P. Wolf, and H. Holman. “Human age and skin physiology shape diversity and abundance of Archaea on skin.” Scientific Reports 7 (2017): 4039.
9 Grice, E.A. and J.A. Segre. “The Human Microbiome: Our Second Genome.” Annual Review of Genomics and Human Genetics (2012).
10 Theelen, B., C. Cafarchia, G. Gaitanis, I.D. Bassukas, T. Boekhout, and T.L. Dawson Jr. “Malassezia ecology, pathophysiology, and treatment.” Medical Mycology 1, no. 56 (2018): 10-25.
11 Levin, N.A. “Beyond Spaghetti and Meatballs: Skin Diseases Associated With the Malassezia Yeasts.” Dermatology Nursing 21, no. 1 (2009).
12 Krestin, D. “The seborrheic facies as a manifestation of post-encephalitic Parkinsonism and allied disorders.” Quarterly Journal of Medicine 21 (1927): 177–186.
13 Broxmeyer, L. “Parkinson’s: another look.” Medical Hypotheses 59, no. 4 (2002): 373-7.
14 Berstad, K. and J.E.R. Berstad. “Parkinson’s disease; the hibernating spore hypothesis. Medical Hypotheses 104 (2017): 48-53.
15 Colcher, A. and T. Simuni. “Parkinson’s Disease and Parkinsonian syndromes: clinical manifestations of Parkinson’s disease.” Medical Clinics of North America 83, no. 2 (1999):327-347.
16 Koller, W. “Does a long preclinical period occur in Parkinson’s disease?” Geriatrics 46, no. 1 (1991): 8-15.
17 Tanner, C.M., K. Albers, S. Goldman S, F. R. Fross, A. Leimpeter, J. Klingman, and S. Van Den Eeden. “Seborrheic dermatitis and risk of future Parkinson’s disease (PD).” Neurology 78, no. 1 (2012).
18 Ravn, A.H., J.P. Thyssen, and A. Egeberg. “Skin disorders in Parkinson's disease: potential biomarkers and risk factors.” Clinical, Cosmetic and Investigational Dermatology 10 (2017): 87-92.
19 Leong, C., A. Buttafuoco, M. Glatz, and P.P. Bosshard. “Antifungal susceptibility testing of Malassezias pp. With an optimized colorimetric broth microdilution method.” Journal of Clinical Microbiology 55, no. 1 (2017): 883–93.
20 Olanow, C.W. and W.C. Koller. “An algorithm (decision tree) for the management of Parkinson’s disease: treatment guidelines.” Neurology 30, no. 3 (1998): 1-57.