Impaired gait and postural instability in patients living with Parkinson’s disease (PD) are regarded as the main aspects of the disease that causes disability in their home and work environment. As a progressive neurological movement disorder due to degeneration in the basal ganglia, PD is the second most common neurological disease after stroke and the fourth most common neuro-degenerative disease in the elderly. Functional Electrical Sensory Stimulation (FESS) (Group 1) and Functional Electrical Sensory and Motor Stimulation (FES&MS) (Group 2) was administered to the common peroneal nerve as external cues to facilitate the initiation of taking a step in patients with akinesia. The hypotheses that were tested were: Hypothesis 1 (H1) FESS and FES&MS decrease freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD. Null Hypothesis (H0) FESS and FES&MS do not decrease freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD. Hypothesis 2 (H2) FESS and FES&MS decrease freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD to such an extent that it improves the quality of life of patients. Null Hypothesis 2 (H02) FESS and FES&MS do not decrease freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD to such an extent that it improves the quality of life of the patients. Hypothesis 3 (H3) FESS decreases freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD more than FES&MS. Null Hypothesis 3 (H03) FESS does not decrease freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD more than FES&MS. A single blind, randomized active controlled clinical trial was conducted. Patients with PD who experienced freezing/akinesia and bradykinesia / hypokinesia and met the inclusion and exclusion criteria of the study were allocated randomly into two groups. Ten (10) patients were randomly allocated to each group. The baseline measurement was determined by calculating the average of the measurements at week zero (0) and week two (2). Results of the participants in each group at week fourteen (14) (after twelve (12) weeks of FESS and FES&MS respectively) were compared to their baseline measurement, as well as between Group 1 and Group 2. The FESS and FES&MS was removed at week fourteen (14) and measurements were repeated at week twenty four (24). Parameters of gait that were used in the trial included; the time, speed, number of steps, average step length, Freezing of gait scale and PCI to complete a walking task. The Qol was determined by using the PDQ-39 and the motor part of the UPDRS. From the results obtained the alternative hypotheses H1, H2 and H3 was accepted for Group 1. The null hypothesis H0 and the alternative hypothesis H3 was accepted for Group 2 It can be concluded from the results of this clinical trial that FESS decreases akinetic episodes in patients with PD statistically significantly and clinically improves their Qol. Qol was statistically significantly improved in Group 2 although hypothesis H1 was not accepted for Group 2. / Dissertation (MPhysT)--University of Pretoria, 2009. / Physiotherapy / unrestricted

Parkinson’s disease (PD) impairs the quality of life of patients and causes substantial social and economic burden. However the currently available symptomatic treatments, although initially effective, do not satisfactorily control the progressive disability experienced by patients with PD in the long run. In order to develop effective treatments for patients that aim to attain the desired effect with as few adverse events as possible, it is crucial to be able to follow and understand the biological mechanisms underlying the continued neural degeneration and treatment failure. The efforts to understand the precise pathway by which neurodegenerative processes proceed and the development of approaches to modulate them offers the promise to eventually enable the prevention of these neurodegenerative diseases. This dissertation focused on two potential synthetic methods to produce pharmaceutical grade Fluorodopa, ultimately to be able to produce positron emitting 18Fluorodopa in South Africa with its potential for studying neuronal mechanisms in the brain. 18Fluorodopa allows a unique almost non-invasive in vivo approach to the evaluation of neurochemical function in the human brain and its local introduction will be a valuable addition to medical research within South Africa’s borders. The successful implementation of safe and efficient non-radioactive models for Fluorodopa synthesis was achieved. The successful demonstration of locally synthesised Fluorodopa safety, as well as a low toxicity profile, both in vitro using cell cultures and in vivo in mouse models was achieved. These were both positive outcomes of objectives set out for this study. Copyright / Dissertation (MSc)--University of Pretoria, 2010. / Pharmacology / unrestricted

Parkinson's disease (PD) is a progressive disorder that affects movement, muscle control and balance. Second only to Alzheimer's disease, PD is one of the most common neurodegenerative disorders in the United States (Lai & Tsui, 2001:135), affecting approximately one million people in the U.S. alone (Parkinson's disease Foundation [PDF], 2009). While the cause of Parkinson's disease remains unknown, there are certain known risk factors associated with the disease. One of the risk factors is increasing age. PD is most frequently associated with older adulthood, affecting one in 100 Americans 60 years and older (PDF). Over the next five decades, the incidence of PD is expected to triple, as the average age of the population increases (Lai & Tsui, 2001:135). Parkinson's disease is a chronic, progressive disorder, with no known cause or promising cure. While substantial information is known about the medical aspect of Parkinson's disease, little is known about the illness experience of living with the disease. The goal of this study was to explore and describe the experiences of people living with Parkinson's disease. The guiding research question was: What are the experiences of people living with Parkinson's disease? A qualitative research approach was followed, with a collective case study research design. The population for this study included people who are in the late stage of Parkinson's disease, thus being diagnosed with Parkinson's disease before 2012 and who are receiving support services from Parkinson's Association of South Africa (PASA). Non-probability purposive sampling was utilized to generate a sample. Ten participants who met the criteria were selected for this study. Semi-structured individual interviews were conducted with participants. Interviews were voice recorded with the permission of the participants and were transcribed. The data gathered were analysed by the researcher and themes and sub-themes were identified. The research findings were presented and critically discussed. Literature control and verbatim quotes were used to support the findings. The conclusions of this study reflected that the experiences of people living with Parkinson's disease are complex. Throughout the study it was found that Parkinson's disease impacts significantly on the physical, psychological and social well-being of people living with this disease in a number of ways. The recommendations offered by this study can be used by professionals working in the field of chronic, geriatric and neurodegenerative illnesses to understand the experiences of people living with Parkinson's disease. / Mini Dissertation (MSW)--University of Pretoria, 2016. / Social Work and Criminology / MSW / Unrestricted

Background: Parkinson's disease (PD) is a debilitating progressive neurological disorder. The main clinical features of PD are: rigidity, bradykinesia, akinesia, and resting tremor. People living with PD often present with impaired gross- and fine upper-limb motor control and ocular tracking. The impaired motor control associated with PD results in difficulty performing basic- and instrumental activities of daily living (BADLs and IADLs). Virtual reality (VR) therapy is an emerging treatment strategy used to address movement impairment in people with neurological diseases, but has not been extensively researched in the rehabilitation of people with PD. This study aimed to determine the effectiveness of VR therapy as a treatment modality for the rehabilitation of upper-limb function during BADLs and IADLs and ocular tracking for people with PD, when compared to conventional physiotherapy. Methods: A single blind randomised control trial was done. Participants were randomly allocated to either the conventional therapy (control) or VR therapy (experimental) groups using the concealed opaque envelope method. Twenty-two participants who gave informed consent were included, if they met the following criteria: Confirmed PD diagnoses; scored above 24/30 for the Mini Mental State Examination; and did not suffer from uncontrolled co-morbid diseases. The control- and experimental groups underwent twelve intervention session of 45 minutes. The control group participated in conventional physiotherapy sessions and the experimental group used the X-box Kinect© VR apparatus during treatment. Participants were assessed at baseline and post-intervention (directly following the 12 session) with the: 9 Hole Peg Test (9HPT), Test d'Evaluation des Membres Superieurs De Personnes Agees (TEMPA) and the King Devick Test. Results: The TEMPA was used to determine unilateral- and bilateral upper-limb function during IADLs and BADLs. Three of the four items of the TEMPA that assessed bilateral upper-limb function indicated statistically significant improvement when the difference between the control and experimental groups were compared post-intervention (Task1 p=0.611; Task 2 p=0.0043; Task 3 p=0.0078; Task 4 p=0.0002). Similarly, three of the four items of the TEMPA that assessed unilateral upper-limb function indicated statistically significant improvement for the experimental group, when compared to the control- group post-intervention (Task 5 p=0.0151; Task 6 p=0.4118; Task 7 p=0.0064; Task 8 p=0.0009). The 9HPT assessed in-hand manipulation and fine upper-limb function. Results from the 9HPT for the left- and right hands of both groups showed clinically significant improvements from baseline to post-intervention, but there was no statistically significant difference between the two groups. The King Devick test was used to assess ocular tracking. The comparison of change between the two groups from baseline to post-intervention on the King Devick did not indicate clinically- or statistically significant change. Discussion and Conclusion: The findings from the bilateral IADL and BADL tasks as measured with the TEMPA are similar to findings in the literature. The results show that VR therapy improve motor control of the upper-limb significantly when both hands work together and when the upper-limbs are moving unilaterally. VR therapy might be more effective than conventional physiotherapy because it allowed for repetitive practice of functional activities, which aided the development of limb control and functional muscle strength. The VR therapy also allowed task-oriented training to occur repetitively. Task-oriented training is known to aid neural plasticity and facilitate functional rehabilitation. The insignificant differences between the groups on the 9HPT is an indication that the task performed for this outcome measure is not specific enough to detect hand function and grip strength. The King Devick test did not indicate change for the control- or experimental groups, which indicates that specific ocular tracking exercises should be included in therapy to address this impairment. / Dissertation (MPhysiotherapy)--University of Pretoria, 2016. / Physiotherapy / MPhysiotherapy / Unrestricted

No description available.

Parkinson's disease (PD) is the second most common chronic neurodegenerative disease characterized by dopamine decrease in the substantia nigra. Currently, there is no promising cure for PD and this has resulted in extensive research into alternative medicines. The aim of this study was to investigate the effect of methanol and ethyl acetate extracts of Lannea schweinfurthii (Engl. Engl) (Anacardiaceae), Zanthoxylum capense (Thunb. Harv) (Rutaceae), Scadoxus puniceus ((L.) Friis & Nordal) (Amaryllidaceae) and Crinum bulbispermum (Burm. f.) Milne-Redh. & Schweick) (Amaryllidaceae) on rotenone-induced toxicity in SH-SY5Y neuroblastoma cells. The latter which mimics PD symptoms in vitro. Cytotoxicity of the plant extracts was assessed using sulforhodamine B (SRB) assay. Intracellular reactive oxygen species (ROS) were measured fluorometrically with the use of the fluorescent dye 2‟,7‟-dichlorodihydrofluorescein diacetate (H2DCF-DA). Intracellular glutathione content was measured fluorometrically after staining with monochlorobimane (MCB). Fluorescent dye 5,5‟ ,6,6‟ -tetrachloro-1,1‟ ,3,3‟ -tetraethylbenzimidazolcarbocyanine iodide (JC-1) was used to assess the mitochondrial membrane potential (MMP) status of cells. Apoptosis was assessed by determining caspase-3 activity through detection of 7-amino-4-methylcoumarin (AMC) which is a product of caspace-3 substrate, acetyl-Asp-Glu-Val-Asp 7-amino-4-methylcoumarin (Ac-DEVD-AMC), cleaved by the caspase-3 enzyme. Rotenone was used as an in vitro model to induce PD-like symptoms. Cytotoxicity studies for methanol extract of Zanthoxylum capense revealed the highest IC50 value of 121.3 μg/mL, indicating low toxicity. The ethyl acetate extract of Crinum bulbispermum was observed to have no effect on the normal proliferation of the SH-SY5Y cells and produced an IC50 value >100 μg/mL. The calculated IC50 value obtained from rotenone cytotoxicity studies was 112 iv nM. Zanthoxylum capense and Scadoxus puniceus plant extracts were observed to be neuroprotective against rotenone-induced toxicity. A decrease in intracellular glutathione content as well as MMP was also observed in cells exposed to rotenone alone (50 nM). There was no intracellular ROS generation observed in cells exposed to rotenone alone (50 nM) after 24 h and 72 h. However, apoptotic cell death was observed in cells treated with rotenone (50 nM). Intracellular ROS production was observed to be elevated by methanol and ethyl acetate extracts of C. bulbispermum. Methanol extracts of Z. capense was observed to increase intracellular glutathione content. MMP was increased effectively following treatment with ethyl acetate extract of C. bulbispermum. Moreover, both methanol and ethyl acetate plant extracts were found to decrease caspase-3 activity significantly (p<0.05), in cells exposed to 50 nM rotenone. Z. capense methanol extract reduced caspase-3 activity the most effectively. Treatment with plant extracts was protective and decreased cell death. Furthermore, L. schweinfurthii, Z. capense, S. puniceus and C. bulbispermum, demonstrated strong antioxidant and anti-apoptotic effects against rotenone-toxicity, making them potential agents in developing therapies for treating PD. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Pharmacology / unrestricted

Thesis (MScMedSC)--Stellenbosch University, 2012. / Bibliography / ENGLISH ABSTRACT: Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. Although the aetiology of PD is still not fully understood, it is thought to involve a combination of environmental (such as exposure to pesticides and neurotoxins) and genetic factors. A number of PD-causing genes have been found including SNCA, LRRK2, EIF4G1 and VPS35 (for autosomal dominant forms of PD) and parkin, PINK1, DJ-1 and ATP13A2 (for autosomal recessive forms of PD – arPD). Mutations in the parkin gene are the predominant cause of arPD. Parkin plays a role in the ubiquitin-proteasomal system which degrades damaged and unwanted proteins in the cell and it is also thought to be involved in maintaining healthy mitochondria. Numerous studies have implicated mitochondrial function in the pathogenesis of PD. Therefore the aim of the present study was to investigate the role of mitochondrial dysfunction in PD patients with parkin-null mutations. Four South African PD patients, each harbouring two parkin-null mutations, were recruited for this study. A muscle biopsy was performed for analysis of mitochondrial morphology using histology and transmission electron microscopy (TEM). Skin biopsies were taken, from which fibroblasts were cultured. These fibroblasts were used in i) mitochondrial morphological assessments using TEM, ii) mitochondrial network analysis, iii) functional studies via ROS measurement and iv) analysis of the proteome using a LTQ Orbitrap Velos mass spectrometer. In addition, RNA was isolated from peripheral blood samples for gene expression studies using the RT² Profiler PCR Array (SABiosciences, USA) and the RT² PCR Primer Assay (SABiosciences, USA). Heterozygous family members (carriers) and wild-type controls were also recruited for this study. Results from the histological and TEM analysis from the muscle biopsy observed subtle mitochondrial changes including the presence of type II fibres, atrophic fibres, the presence of lipids, and wrinkling of the sarcolemmal membrane. Enlarged mitochondria were also observed in one patient. TEM analysis on the patient’s fibroblasts observed an increase in the number of electron dense vacuoles, speculated to be autolysosomes. The mitochondrial network in two of the patients’ fibroblasts showed fragmented and dot-like networks which are indicative of damaged mitochondria. An increase in mitochondrial ROS levels was observed in three of the four patients. Expression studies found down-regulation of 14 genes from four of the five mitochondrial complexes and a total of 688 proteins were found only in the control and not in the patient fibroblasts. Some of these proteins are known to be part of the ‘mitochondrial dysfunction’ pathway. Taken together, these results indicate that the absence of parkin results in a number of mitochondrial alterations. Based on these findings, a model of PD was proposed: It is speculated that when parkin is absent, electron transport chain complex genes are down-regulated. This results in impaired oxidative phosphorylation, causing an increase in the production of mitochondrial ROS and subsequent oxidative stress. Mitochondria are then damaged; resulting in the fragmentation of the mitochondrial network. The impaired mitochondria are thus tagged for degradation, causing the recruitment of autolysosomes which engulf the mitochondria via mitophagy. Ultimately, as the compensatory mechanisms fail, this triggers the consequential cascade of cellular apoptotic events. This study has elucidated the effect of parkin on the mitochondria, and can act as a ‘stepping stone’ towards future development of therapeutic strategies and/or biochemical markers that will benefit not only patients with PD but also other neurodegenerative disorders. / AFRIKAANSE OPSOMMING: Parkinson se siekte (PS) is ‘n neurodegeneratiewe bewegings-afwyking gedefineer deur die verlies van dopaminergiese neurone in die substantia nigra van die midde brein. Alhoewel die spesifieke oorsprong van die afwyking nog nie ten volle begryp is nie, word bydraes van beide omgewings faktore (bv. blootstelling aan plaagdoders en neurotoksienes) asook genetiese faktore gespekuleer. Vanuit ‘n genetiese aspek is ‘n aantal gene al geassosieer met PS. Hierdie gene sluit in SNCA, LRRK2, EIF4G1 en VPS35 (vir outosomale dominante vorms van PS) en parkin, PINK1, DJ-1, en ATP13A2 (vir outosomale resessiewe vorms van PS - orPS). Mutasies in die parkin geen is aangedui as die hoof oorsaak van orPS. Parkin speel ‘n rol in die ubiquitine-proteasomale sisteem wat beskadige en ongewensde proteïne binne in die sel verwyder en is verdink om by te dra tot die instandhouding van gesonde mitokondria. Mitokondriese wanfunksionering is ook deur talle studies gewys as ‘n bydraende faktor in die patologie van PS. Die doel van die studie is om ondersoek in te stel tot die spesifieke rol wat mitokondriese wanfunsionering speel in PS pasiënte met parkin-nul mutasies. Vier Suid-Afrikaanse PS-pasiënte, elk met twee parkin-nul mutasies, is gebruik vir die studie. Deur middel van spierbiopsies is monsters verkry vir mitokondriese morfologiese analises met behulp van histologiese en elektron-oordrag mikroskopie tegnieke (TEM). Vel biopsies is ook geneem en fibroblaste is gekweek vir die gebruik in: i) mitokondriese morfologiese assesering; ii) mitokondriese netwerk analiese; iii) funksionele studies waar vlakke van reaktiewe suurstof spesies (ROS) gemeet is; iv) proteoom analiese met behup van ‘n LTQ Orbitrap Velos massa spektrometer. RNA is ook geisoleer vanaf perifere bloedmonsters vir die gebruik in geen-uitdrukkings studies met behulp van ‘n RT² Profiler PCR Array en ‘n RT² Primer Assay. Selle vanaf famielie lede wat heterosigotiese draers is van die mutasie, asook normale (geen parkin mutasie) selle is gebruik as kontroles in die studie. TEM resultate vanaf die spier monsters het subtiele mitokondriese veranderinge getoon. Hierdie sluit in die teenwoordigheid van tipe II vesels, atrofiese vesels, teenwoordigheid van lipiedes, assook waarnemings van rimpeling van die sarcolemmal membraan. Vergrote mitokondrias is ook in een van die pasiënte opgelet. TEM resultate vanaf die fibroblaste het toename in die aantal elektron-digte vakuole vertoon, moontlik geidentifiseer as autolisosome. Gefragmenteerde en onderbreekte mitokondria netwerke is gelet tydens netwerk analiese van die fibroblaste, ‘n indikasie van beskadigde mitokondria. ‘n Toename in mitokondriese ROS vlakke is gevind in drie van die vier pasiënte. Af-regulering van 14 gene, geassosieerd met vier uit die vyf mitokondria komplekse, is verneem tydens die geen-uitdrukkings studie. Saam met dit is ‘n totaal van 688 proteïene geidentifiseer wat slegs teenwoordig is in die kontrole monsters en nie in die pasiënt monsters nie. Hierdie proteïene is almal uitgedruk en betrokke in die mitokondriese wanfunsionerings-weë. Hierdie resultate dui dat die afwesigheid van parkin mitokondriese afwykings tot gevolg het wat kan lei tot die afsterwing van selle. Dit dra ook by tot die vorming van ‘n beter-verstaande siekte-model vir PS: Mutasies in parkin (wat lei tot die afwesigheid van parkin) kan dus moontlik lei tot die af-regulasie van gene geassosieerd met die elektron-vervoer ketting komplekse in die mitokondria. Dit lei tot gebrekkige oksidatiewe fosforilering en veroorsaak ‘n toename in die vorming van ROS, wat dan ‘n toename in oksidatiewe stres binne in die sel tot gevolg het. Uiteindelik lei dit dus tot die beskadiging van die mitokondria wat gepaard gaan met fragmentering van die mitokondriese netwerk. Beskadigde mitokondrias word geetiketeer vir afbraking. Hierdie etiketering aktiveer omringende autophagosome wat die beskadigde mitokondrias dan verwyder deur middel van ‘n verswelgende proses genaamd mitophagy. Dit veroorsaak die aktivering van ‘n aantal gekorreleerde sellulêre prosesse wat lei tot apoptose (afsterwing van die sel). Hierdie studie dra by tot die verklaring van die spesifieke effek wat parkin mutasies het op die funksionering van die mitokondria. Resultate hier lê ook die grondslag vir toekomstige studies met die doel tot die ontwikkeling van terapeutiese strategeë en biochemiese merkers wat kan bydrae tot die genesing van beide pasiënte met PS, asook pasiënte met ander neurodegeneratiewe afwykings.

The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology. This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease. A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD. Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a Drosophila model of AD. Lysozyme was found to alter the aggregation pathway of Aβ1-42, to counteract the formation of toxic Aβ species and to protect from Aβ1-42 induced cell toxicity. Aβ1-42 in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity. LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ1-42 caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ1-42, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ1-42. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion. In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.

In patients with Parkinson’s disease (PD), the molecularly misfolded form of α-synuclein was recently identified in cutaneous autonomic nerve fibers which displayed increased accumulation even in early disease stages. However, the underlying mechanisms of synucleinopathic nerve damage and its implication for brain pathology in later life remain to be elucidated. To date, specific diagnostic tools to evaluate small fiber pathology and to discriminate neurodegenerative proteinopathies are rare. Recently, research has indicated that deposition of α-synuclein in cutaneous nerve fibers quantified via immunohistochemistry in superficial skin biopsies might be a valid marker of PD which could facilitate early diagnosis and monitoring of disease progression. However, lack of standardization of techniques to quantify neural α-synuclein deposition limits their utility in clinical practice. Additional challenges include the identification of potential distinct morphological patterns of intraneural α-synuclein deposition among synucleinopathies to facilitate diagnostic discrimination and determining the degree to which structural damage relates to dysfunction of nerve fibers targeted by α-synuclein. Answering these questions might improve our understanding of the pathophysiological role of small fiber neuropathy in Parkinson’s disease, help identify new treatment targets, and facilitate assessment of response to neuroprotective treatment.

In patients with Parkinson’s disease (PD), the molecularly misfolded form of α-synuclein was recently identified in cutaneous autonomic nerve fibers which displayed increased accumulation even in early disease stages. However, the underlying mechanisms of synucleinopathic nerve damage and its implication for brain pathology in later life remain to be elucidated. To date, specific diagnostic tools to evaluate small fiber pathology and to discriminate neurodegenerative proteinopathies are rare. Recently, research has indicated that deposition of α-synuclein in cutaneous nerve fibers quantified via immunohistochemistry in superficial skin biopsies might be a valid marker of PD which could facilitate early diagnosis and monitoring of disease progression. However, lack of standardization of techniques to quantify neural α-synuclein deposition limits their utility in clinical practice. Additional challenges include the identification of potential distinct morphological patterns of intraneural α-synuclein deposition among synucleinopathies to facilitate diagnostic discrimination and determining the degree to which structural damage relates to dysfunction of nerve fibers targeted by α-synuclein. Answering these questions might improve our understanding of the pathophysiological role of small fiber neuropathy in Parkinson’s disease, help identify new treatment targets, and facilitate assessment of response to neuroprotective treatment.