Salivary Biomarkers of Parkinson's disease

This blog post marks the publication of our first paper on ‘salivary biomarkers of Parkinson’s disease’, resulting from a collaboration between the PREDICT-PD group and the saliva research laboratories at King’s College London.

Biomarkers are measurable indicators of the severity or presence of a particular disease. For example, blood cholesterol levels are a useful biomarker for risk of heart attack or stroke. As of yet, there are no such biomarkers for Parkinson’s disease but having some sort measurable biological indicator would be useful to help achieve earlier diagnosis, to monitor the progression of the disease or even to monitor the response to new treatments in clinical trials aimed at slowing the progression of the disease. Such a biomarker could one day be used alongside the online survey tools being developed as part of the PREDICT-PD project to help identify people with a high risk of developing Parkinson’s disease over the next few years.

Saliva may be an ideal fluid in which to look for biomarkers of Parkinson’s disease for two main reasons. First, collection of saliva is relatively easy compared with taking a blood sample (and certainly much less uncomfortable than having a lumbar puncture to collect spinal fluid!) Second, there are good reasons to believe that saliva may actually be affected in Parkinson’s disease. Some patients with Parkinson’s report that they experience dry mouth, excessive saliva and drooling or that their saliva has become particularly sticky and can stain clothes. There is also evidence that the nerves involved in the control of the saliva glands are affected in Parkinson’s disease.

A test for Parkinson's disease based on saliva would be cheaper, easier to perform and much more acceptable to patients than a test requiring a lumbar puncture to collect cererbro-spinal fluid!

With this in mind, we conducted a small pilot study by collecting saliva from 16 patients with Parkinson’s and 22 control participants of a similar age to the patients and then performed a variety of tests to compare the composition of the saliva from the two groups.

We found that there was more protein in the saliva of patients with Parkinson’s disease. Further tests indicated that the source of this additional protein appeared to be the ‘major’ salivary glands and that the additional protein in patient saliva could reflect a dysfunction of the nerves involved in the control of these major salivary glands (which we know from previous studies to be affected in Parkinson’s disease).

We also found that among the patients with Parkinson’s disease, a specific protein in the saliva, called ‘DJ-1’, appeared to correlate with the severity of their disease (specifically, salivary DJ-1 correlated with a Parkinson’s disease severity rating scale called the UPDRS score). This was particularly interesting because DJ-1 is a protein which we already know to be involved in the process that leads to degeneration of neurons in PD. In addition, DJ-1 has previously been shown to be a potential biomarker of Parkinson’s disease in the blood and in the cerebro-spinal fluid (the fluid which bathes the brain and the spinal cord).

(a) The saliva of patients with PD contained more protein than the saliva of patients with controls. (b) The salivary concentration of a protein called DJ-1 correlated with disease severity (measured by UPDRS score)

By finding that interesting difference exist between the saliva of patients with Parkinson’s disease and controls we believe we have strengthened the case that saliva may be an ideal fluid for further biomarker discovery work. Our ambition is that one day a saliva-based test could be used (alongside the other tools being developed as part of the PREDICT-PD project) to help identify people at high risk of – or even help diagnose – Parkinson’s disease.

Elevated salivary protein in Parkinson’s disease and salivary DJ-1 as a potential marker of disease severity

Parkinsonism and Related Disorders 2015 Published online: July 23, 2015 DOI: http://dx.doi.org/10.1016/j.parkreldis.2015.07.021

Joseph M. Masters, Alastair J. Noyce, Thomas T. Warner, Gavin Giovannoni, Gordon B. Proctor

Abstract

Introduction:
There is an urgent need to identify robust biomarkers for Parkinson’s disease (PD). Previous studies have shown changes in composition and secretion of saliva in patients with PD, including an increase in salivary DJ-1 concentration. Autonomic dysfunction is a known feature of PD and could contribute to abnormal saliva gland function.

Methods:

In this pilot cross-sectional study, characterisation of the saliva of 16 patients with PD and 22 age-matched controls was performed. Salivary DJ-1 concentration was measured with quantitative immunoblotting; total protein concentration with a BCA assay and spectrophotometry; amylase with an amylase activity assay; albumin with an ELISA and mucin concentration with periodic-acid Schiff staining of SDS-gels.

Results:

Patient saliva showed an increase in both total protein concentration (8.4 vs 5.0 mg/ml, p=0.0002) and DJ-1 concentration (0.84 vs 0.42 μg/ml, p=0.001), but there was no difference in salivary DJ-1 after adjusting for total protein concentration. In patients, adjusted DJ-1 levels correlated with disease severity measured with the MDS-Unified Parkinson’s Disease Rating Scale (p=0.019). Patient saliva had elevated concentrations of amylase (127 vs 64 units/ml, p=0.0005) and albumin (110 vs 41 μg/ml, p=0.0003) but not mucins.

Conclusions:

This study suggests that the saliva of patients with PD is different in composition to that of healthy age-matched controls, supporting the notion that saliva may be a good candidate for biomarker discovery in PD. The specific differences suggest that major salivary glands and gingival crevice fluid may both be sources of additional DJ-1 and protein in patient saliva.

Masters, J., Noyce, A., Warner, T., Giovannoni, G., & Proctor, G. (2015). Elevated salivary protein in Parkinson’s disease and salivary DJ-1 as a potential marker of disease severity Parkinsonism & Related Disorders DOI: 10.1016/j.parkreldis.2015.07.021

Glitazone Treatment and Incidence of Parkinson's Disease among People with Diabetes: A Retrospective Cohort Study

This is an interesting observational study of the negative association of Parkinson's with PPARɣ agonists in diabetic patients... it suggests that those on PPARɣ agonists are less likely to be diagnosed with Parkinson's. Whilst this is an interesting finding, I see two main problems... patients that are diagnosed with PD within 1-2 years (at least!) of being included in the study should have been dropped from the analysis, given the disease is highly likely to be present for quite a number of years before diagnosis...undiagnosed PD will likely bias the results. The other important point is that a recent phase 2 study of pioglitazone in PD had negative findings (see http://predictpd.blogspot.co.uk/2015/06/pioglitazone-in-early-parkinsons.html)

Other than these observations, this is an important study and these drugs should be looked at closely to see if they affect Parkinson's disease course...

PLoS Med. 2015 Jul 21;12(7):e1001854. doi: 10.1371/journal.pmed.1001854. eCollection 2015.

Brauer R, Bhaskaran K, Chaturvedi N, Dexter DT, Smeeth L, Douglas I.

http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001854

BACKGROUND:

Recent in vitro and animal experiments suggest that peroxisome proliferation-activated receptor gamma (PPARɣ) agonist medications, such as antidiabetic glitazone (GTZ) drugs, are neuroprotective in models of Parkinson's disease (PD). These findings have not been tested in humans. We hypothesized that individuals prescribed GTZ drugs would have a lower incidence of PD compared to individuals prescribed other treatments for diabetes.

METHODS AND FINDINGS:

Using primary care data from the United Kingdom Clinical Practice Research Datalink (CPRD), we conducted a retrospective cohort study in which individuals with diabetes who were newly prescribed GTZ (GTZ-exposed group) were matched by age, sex, practice, and diabetes treatment stage with up to five individuals prescribed other diabetes treatments (other antidiabetic drug-exposed group). Patients were followed up from 1999 until the first recording of a PD diagnosis, end of observation in the database, or end of the study (1 August 2013). An incidence rate ratio (IRR) was calculated using conditional Poisson regression, adjusted for possible confounders. 44,597 GTZ exposed individuals were matched to 120,373 other antidiabetic users. 175 GTZ-exposed individuals were diagnosed with PD compared to 517 individuals in the other antidiabetic drug-exposed group. The incidence rate (IR) of PD in the GTZ-exposed group was 6.4 per 10,000 patient years compared with 8.8 per 10,000 patient years in those prescribed other antidiabetic treatments (IRR 0.72, 95% confidence interval [CI] 0.60-0.87). Adjustments for potential confounding variables, including smoking, other medications, head injury, and disease severity, had no material impact (fully adjusted IRR 0.75, 0.59-0.94). The risk was reduced in those with current GTZ prescriptions (current GTZ-exposed IRR 0.59, 0.46-0.77) but not reduced among those with past prescriptions (past GTZ-exposed IRR 0.85, 0.65-1.10). Our study only included patients with diabetes who did not have a PD diagnosis when they were first prescribed GTZ, and thus, it cannot establish whether GTZ use prevents or slows the progression of PD.

CONCLUSIONS:

In patients with diabetes, a current prescription for GTZ is associated with a reduction in incidence of PD. This suggests PPAR gamma pathways may be a fruitful drug target in PD.

Association Between Parkinson Disease and Risk of Cancer in Taiwan

The results of this study are largely at odds with the previous literature except for associations with melanoma and prostate cancer... this reason may lie in ethnic and regional differences in determinants of PD and cancer...

JAMA Oncol. 2015 Jun 18. doi: 10.1001/jamaoncol.2015.1752. [Epub ahead of print]

Lin PY, Chang SN, Hsiao TH, Huang BT, Lin CH, Yang PC.

IMPORTANCE:

Parkinson disease (PD) has been reported to be associated with a general reduced risk of cancer. These studies were mainly carried out in Western populations and little was known about associations in East Asians.

OBJECTIVE:

To analyze the association between PD and risk of cancer.

DESIGN, SETTING, AND PARTICIPANTS:

In this cohort study, the data were obtained from the Taiwan National Health Insurance Research Database, which contained information on approximately 24.7 million insured individuals. The cohort included individuals with newly diagnosed as having PD between 2004 and 2010. An age- and sex-matched systematic random-sampling method was used for subject selection in the reference non-PD cohort. Multivariate Cox proportional hazard regression analysis was used to determine the effects of PD on the risks of cancer, as shown by hazard ratios (HRs) with 95% CIs.

MAIN OUTCOMES AND MEASURES:

The Taiwan Population Census and National Cancer Registry Databases were used to identify patients with cancer. The last follow-up date was December 31, 2012.

RESULTS:

In 62 023 patients with PD, the HR for all subsequent cancers combined was 1.58 (95% CI, 1.50-1.65). Of the 19 types of cancer, Parkinson disease was not associated with breast, ovarian, or thyroid cancers. Increased HRs were found in the remaining 16 cancers, including malignant brain tumors (HR, 3.42; 95% CI, 1.84-6.38), gastrointestinal tract cancers (esophageal [HR, 1.81; 95% CI, 1.28-2.57], stomach [HR, 1.59; 95% CI, 1.30-1.94], colorectal [HR, 1.47; 95% CI, 1.31-1.65], liver [HR, 1.89; 95% CI, 1.67-2.14]; gallbladder [HR, 1.73; 95% CI, 1.16-2.57], and pancreas [HR, 1.48; 95% CI, 1.09-2.02]) (P < .05 for all comparisons), lung cancers (HR, 1.56; 95% CI, 1.38-1.76), some hormone-related cancers (uterine [HR, 1.83; 95% CI, 1.12-3.01], cervical [HR, 1.36; 95% CI, 1.05-1.76], and prostate [HR, 1.80; 95% CI, 1.52-2.13; P < .05 for all comparisons), urinary tract cancers (kidney and bladder cancers; HRs, 1.59 and 1.99, respectively; P < .001 for both comparisons), lymphoma and/or leukemia (HR, 1.62; 95% CI, 1.31-2.01), melanoma (HR, 2.75; 95% CI, 1.35-5.59), and other skin cancers (HR, 1.81; 95% CI, 1.46-2.23). For hepatocellular carcinoma, the highest HR resided in the 50- to 59-year-old group (HR, 2.57; 95% CI, 1.7-3.89).

CONCLUSIONS AND RELEVANCE:

Our study concludes that PD is is associated with most cancers in Taiwan. Further studies are needed to clarify whether our findings can be applied to other East Asian populations. The differences between our study and most previous cohorts suggest the importance of ethnicity and environmental exposures in disease pathogenesis.

Colonic bacterial composition in Parkinson's disease

Latest report on the microbiome and PD...

Mov Disord. 2015 Jul 16. doi: 10.1002/mds.26307. [Epub ahead of print]

Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, Mutlu E, Shannon KM.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26307/abstract

INTRODUCTION:

We showed that Parkinson's disease (PD) patients have alpha-synuclein (α-Syn) aggregation in their colon with evidence of colonic inflammation. If PD patients have altered colonic microbiota, dysbiosis might be the mechanism of neuroinflammation that leads to α-Syn misfolding and PD pathology.

METHODS:

Sixty-six sigmoid mucosal biopsies and 65 fecal samples were collected from 38 PD patients and 34 healthy controls. Mucosal-associated and feces microbiota compositions were characterized using high-throughput ribosomal RNA gene amplicon sequencing. Data were correlated with clinical measures of PD, and a predictive assessment of microbial community functional potential was used to identify microbial functions.

RESULTS:

The mucosal and fecal microbial community of PD patients was significantly different than control subjects, with the fecal samples showing more marked differences than the sigmoid mucosa. At the taxonomic level of genus, putative, "anti-inflammatory" butyrate-producing bacteria from the genera Blautia, Coprococcus, and Roseburia were significantly more abundant in feces of controls than PD patients. Bacteria from the genus Faecalibacterium were significantly more abundant in the mucosa of controls than PD. Putative, "proinflammatory" Proteobacteria of the genus Ralstonia were significantly more abundant in mucosa of PD than controls. Predictive metagenomics indicated that a large number of genes involved in metabolism were significantly lower in the PD fecal microbiome, whereas genes involved in lipopolysaccharide biosynthesis and type III bacterial secretion systems were significantly higher in PD patients.

CONCLUSION:

This report provides evidence that proinflammatory dysbiosis is present in PD patients and could trigger inflammation-induced misfolding of α-Syn and development of PD pathology.

Heterozygote carriers for CNVs in PARK2 are at risk of PD

Whether heterozygous carriers of PARK2 mutations are at increased risk of PD has been a controversial topic in recent years. Here is some evidence that heterozygous CNV carriers (note not mutations) may be at elevated risk of Parkinson's...

Hum Mol Genet. 2015 Jul 17. pii: ddv277. [Epub ahead of print]

Huttenlocher J, Stefansson H, Steinberg S, Helgadottir HT, Sveinbjörnsdóttir S, Riess O, Bauer P, Bauer P.

http://hmg.oxfordjournals.org/content/early/2015/07/16/hmg.ddv277.abstract

Together with point mutations, homozygous deletions or duplications in PARK2 are responsible for the majority of autosomal recessive juvenile Parkinsonism. It is debated, however, whether heterozygous carriers of these mutations are at increased risk of Parkinson's disease (PD).Our goal was to determine whether heterozygous carriers of copy number variants (CNVs) affecting exons of the PARK2 gene are at risk of PD that is greater than that of non-carriers.We searched for CNVs affecting exons of PARK2 in a sample of 105,749 genotyped Icelanders. In total 989 carriers, including 24 diagnosed with PD, were identified. The heterozygous carriers were tested for association in a sample of 1,415 PD patients and 40,474 controls≥65 years of age. PD patients were more often heterozygous carriers of PARK2 CNVs than controls (OR=1.69, P=0.03) and compound heterozygous PD patients for a CNV and a missense mutation were not found. Furthermore we conducted a meta-analysis of studies reporting on case-control samples screened for heterozygous PARK2 CNVs. Ten studies were included in the final analysis, with 4,538 cases and 4,213 controls. The pooled OR and P-value for the published and Icelandic results showed significant association between PARK2 CNVs and risk of PD (OR=2.11, P=2.54 x 10-6).Our analysis shows that heterozygous carriers of CNVs affecting exons of PARK2 have greater risk of PD than non-carriers.

Baseline and longitudinal grey matter changes in newly diagnosed Parkinson's disease: ICICLE-PD study

Important imaging marker correlate for mild cognitive impairment in PD...

Brain. 2015 Jul 14. pii: awv211. [Epub ahead of print]

Mak E, Su L, Williams GB, Firbank MJ, Lawson RA, Yarnall AJ, Duncan GW, Owen AM, Khoo TK, Brooks DJ, Rowe JB, Barker R, Burn DJ, O'Brien JT.

http://brain.oxfordjournals.org/content/early/2015/07/13/brain.awv211.long

Mild cognitive impairment in Parkinson's disease is associated with progression to dementia (Parkinson's disease dementia) in a majority of patients. Determining structural imaging biomarkers associated with prodromal Parkinson's disease dementia may allow for the earlier identification of those at risk, and allow for targeted disease modifying therapies. One hundred and five non-demented subjects with newly diagnosed idiopathic Parkinson's disease and 37 healthy matched controls had serial 3 T structural magnetic resonance imaging scans with clinical and neuropsychological assessments at baseline, which were repeated after 18 months. The Movement Disorder Society Task Force criteria were used to classify the Parkinson's disease subjects into Parkinson's disease with mild cognitive impairment (n = 39) and Parkinson's disease with no cognitive impairment (n = 66). Freesurfer image processing software was used to measure cortical thickness and subcortical volumes at baseline and follow-up. We compared regional percentage change of cortical thinning and subcortical atrophy over 18 months. At baseline, cases with Parkinson's disease with mild cognitive impairment demonstrated widespread cortical thinning relative to controls and atrophy of the nucleus accumbens compared to both controls and subjects with Parkinson's disease with no cognitive impairment. Regional cortical thickness at baseline was correlated with global cognition in the combined Parkinson's disease cohort. Over 18 months, patients with Parkinson's disease with mild cognitive impairment demonstrated more severe cortical thinning in frontal and temporo-parietal cortices, including hippocampal atrophy, relative to those with Parkinson's disease and no cognitive impairment and healthy controls, whereas subjects with Parkinson's disease and no cognitive impairment showed more severe frontal cortical thinning compared to healthy controls. At baseline, Parkinson's disease with no cognitive impairment converters showed bilateral temporal cortex thinning relative to the Parkinson's disease with no cognitive impairment stable subjects. Although loss of both cortical and subcortical volume occurs in non-demented Parkinson's disease, our longitudinal analyses revealed that Parkinson's disease with mild cognitive impairment shows more extensive atrophy and greater percentage of cortical thinning compared to Parkinson's disease with no cognitive impairment. In particular, an extension of cortical thinning in the temporo-parietal regions in addition to frontal atrophy could be a biomarker in therapeutic studies of mild cognitive impairment in Parkinson's disease for progression towards dementia.

Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers

Interesting observations in manifesting and non-manifesting LRRK2 carriers...

PLoS One. 2015 Jul 15;10(7):e0132368. doi: 10.1371/journal.pone.0132368.

Pont-Sunyer C, Iranzo A, Gaig C, Fernández-Arcos A, Vilas D, Valldeoriola F, Compta Y, Fernández-Santiago R, Fernández M, Bayés A, Calopa M, Casquero P, de Fàbregues O, Jaumà S, Puente V, Salamero M, José Martí M, Santamaría J, Tolosa E.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132368

OBJECTIVE:

In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC).

METHODS:

A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD.

RESULTS:

Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC.

CONCLUSIONS:

Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.

Delineating nonmotor symptoms in early Parkinson's disease and first-degree relatives

Large UK observational study describing the range of non motor features in a large cohort of PD subjects, 1st degree relatives and controls...

Mov Disord. 2015 Jul 14. doi: 10.1002/mds.26281. [Epub ahead of print]

Baig F, Lawton M, Rolinski M, Ruffmann C, Nithi K, Evetts SG, Fernandes HR, Ben-Shlomo Y, Hu MT.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26281/abstract

Abstract

Nonmotor symptoms (NMS) are an important prodromal feature of Parkinson's disease (PD). However, their frequency, treatment rates, and impact on health-related quality of life (HRQoL) in the early motor phase is unclear. Rates of NMS in enriched at-risk populations, such as first-degree PD relatives, have not been delineated. We assessed NMS in an early cohort of PD, first-degree PD relatives and control subjects to address these questions. In total, 769 population-ascertained PD subjects within 3.5 years of diagnosis, 98 first-degree PD relatives, and 287 control subjects were assessed at baseline across the following NMS domains: (1) neuropsychiatric; (2) gastrointestinal; (3) sleep; (4) sensory; (5) autonomic; and (6) sexual. NMS were much more common in PD, compared to control subjects. More than half of the PD cases had hyposmia, pain, fatigue, sleep disturbance, or urinary dysfunction. NMS were more frequent in those with the postural instability gait difficulty phenotype, compared to the tremor dominant (mean total number of NMS 7.8 vs. 6.2; P < 0.001). PD cases had worse HRQoL scores than controls (odds ratio: 4.1; P < 0.001), with depression, anxiety, and pain being stronger drivers than motor scores. NMS were rarely treated in routine clinical practice. First-degree PD relatives did not significantly differ in NMS, compared to controls, in this baseline study. NMS are common in early PD and more common in those with postural instability gait difficulty phenotype or on treatment. Despite their major impact on quality of life, NMS are usually under-recognized and untreated. 

The Effect of Visual Feedback on Writing Size in Parkinson's Disease

The change in handwriting is one of the intriguing features of Parkinson's (and also an extremely frustrating one)...the time it begins is of particular interest...

Parkinsons Dis. 2015;2015:857041. doi: 10.1155/2015/857041. Epub 2015 Jun 17.

Potgieser AR, Roosma E, Beudel M, de Jong BM.

Parkinson's disease (PD) leads to impairment in multiple cognitive domains. Micrographia is a relatively early PD sign of visuomotor dysfunction, characterized by a global reduction in writing size and a decrement in size during writing. Here we aimed to investigate the effect of withdrawal of visual feedback on writing size in patients with PD. Twenty-five patients with non-tremor-dominant PD without cognitive dysfunction and twenty-five age-matched controls had to write a standard sentence with and without visual feedback. We assessed the effect of withdrawal of visual feedback by measuring vertical word size (i), horizontal length of the sentence (ii), and the summed horizontal word length without interspacing (iii), comparing patients with controls. In both patients and controls, writing was significantly larger without visual feedback. This enlargement did not significantly differ between the groups. Smaller handwriting significantly correlated with increased disease severity. Contrary to previous observations that withdrawal of visual feedback caused increased writing size in specifically PD, we did not find differences between patients and controls. Both groups wrote larger without visual feedback, which adds insight in general neuronal mechanisms underlying the balance between feed-forward and feedback in visuomotor control, mechanisms that also hold for grasping movements.

Distinctive Distribution of phospho-alpha-synuclein in dermal nerves in multiple system atrophy

Further evidence that synucleinopathies may be detectable in skin biopsies...and if they can be differentiated from one another, then all the better...would be interesting to know at what stage phospho-alpha-syn starts being deposited...

Mov Disord. 2015 Jul 14. doi: 10.1002/mds.26293. [Epub ahead of print]

Doppler K, Weis J, Karl K, Ebert S, Ebentheuer J, Trenkwalder C, Klebe S, Volkmann J, Sommer C.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26293/abstract;jsessionid=D1A509FE0389AC6375D82E0697C82CDE.f02t04

BACKGROUND:

MSA is characterized by deposition of alpha-synuclein (α-Syn) in oligodendrocytes and central nervous system (CNS) neurons. After recently detecting phospho-α-Syn (p-α-Syn) in dermal nerve fibers of patients with Parkinson's disease (PD), we assessed skin biopsies from patients with MSA to evaluate its potential role as a biomarker.

METHODS:

Skin biopsies of patients with MSA (n = 12), idiopathic PD (n = 30), tauopathies (n = 15), and normal controls (n = 39) were analyzed. P-α-Syn within dermal nerves was detected by immunofluorescence staining.

RESULTS:

p-α-Syn was found in 67% of patients with MSA and Parkinson's disease, but not in patients with tauopathy or controls when analyzing 15 consecutive sections. Sensitivity could be increased to 75% and 73%, respectively, by analyzing serial sections. In contrast to PD, where p-α-Syn clustered in autonomic fibers, deposits were mainly found in unmyelinated somatosensory fibers in MSA.

CONCLUSION:

α-Syn pathology in MSA is not restricted to the CNS, and skin biopsy may be useful for the premortem study of p-α-Syn. © 2015 International Parkinson and Movement Disorder Society.

Long-Term Follow-up Investigation of Isolated Rapid Eye Movement Sleep Without Atonia Without Rapid Eye Movement Sleep Behavior Disorder: A Pilot Study

First evidence that RWA may also be a risk marker for future PD....

J Clin Sleep Med. 2015 Jun 22. pii: jc-00066-15. [Epub ahead of print]

Stefani A, Gabelia D, Högl B, Mitterling T, Mahlknecht P, Stockner H, Poewe W, Frauscher B.

STUDY OBJECTIVES:

Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a harbinger of synuclein-mediated neurodegenerative diseases. It is unknown if this also applies to isolated REM sleep without atonia (RWA). We performed a long-term follow-up investigation of subjects with isolated RWA.

METHODS:

Participants were recruited from 50 subjects with isolated RWA who were identified at the sleep laboratory of the Department of Neurology at Innsbruck Medical University between 2003 and 2005. Eligible subjects underwent follow-up clinical examination, polysomnography, and assessment of neurodegenerative biomarkers (cognitive impairment, finger speed deficit, impaired color vision, olfactory dysfunction, orthostatic hypotension, and substantia nigra hyperechogenicity).

RESULTS:

After a mean of 8.6 ± 0.9 y, 1 of 14 participating subjects (7.3%) progressed to RBD. Ten of 14 RWA subjects (71.4%) were positive for at least one neurodegenerative biomarker. Substantia nigra hyperechogenicity and presence of mild cognitive impairment were both present in 4 of 14 subjects with isolated RWA. Electromyographic activity measures increased significantly from baseline to follow-up polysomnography ("any" mentalis and both anterior tibialis muscles: 32.5 ± 9.4 versus 52.2 ± 16.6%; p = 0.004).

CONCLUSION:

This study provides first evidence that isolated RWA is an early biomarker of synuclein-mediated neurodegeneration. These results will have to be replicated in larger studies with longer observational periods. If confirmed, these disease findings have implications for defining at-risk cohorts for Parkinson disease.