Monday, 27 July 2015
Nice review of disease modifying approaches in PD...
Mov Disord. 2015 Jul 24. doi: 10.1002/mds.26354. [Epub ahead of print]
Kalia LV, Kalia SK, Lang AE.
Parkinson's disease (PD) is an increasingly prevalent and progressively disabling neurodegenerative disease. The impact of PD on patients and their families as well as its burden on health care systems could be substantially reduced by disease-modifying therapies that slow the rate of neurodegeneration or stop the disease process. Multiple agents have been studied in clinical trials designed to assess disease modification in PD, but all have failed. Over the last 3 years, clinical trials investigating the potential of adeno-associated virus serotype 2 (AAV)-neuturin, coenzyme Q10, creatine, pramipexole, and pioglitazone reported negative findings or futility. Despite these disappointments, progress has been made by expanding our understanding of molecular pathways involved in PD to reveal new targets, and by developing novel animal models of PD for preclinical studies. Currently, at least eight ongoing clinical trials are testing the promise of isradipine, caffeine, nicotine, glutathione, AAV2-glial cell-line derived neurotrophic factor (GDNF), as well as active and passive immunization against α-synuclein (α-Syn). In this review, we summarize the clinical trials of disease-modifying therapies for PD that were published since 2013 as well as clinical trials currently in progress. We also discuss promising approaches and ongoing challenges in this area of PD research.
Friday, 24 July 2015
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
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.
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.
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.
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.
Thursday, 23 July 2015
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.
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.
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.
Wednesday, 22 July 2015
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.
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.
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.
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.
Tuesday, 21 July 2015
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.
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.
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.
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.
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.
Monday, 20 July 2015
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.
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.
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.
Sunday, 19 July 2015
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.
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).
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.
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.
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.
Saturday, 18 July 2015
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.
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 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.
Friday, 17 July 2015
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.
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.
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.
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.
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.
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.
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).
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).
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.
Thursday, 16 July 2015
Further evidence that some staining for alpha-syn can be seen resected GI tissue but that staining patterns may differ between patients and controls...and this in itself may hold more promise as a biomarker than simply the presence of alpha-syn alone...
Neurosci Lett. 2015 Jul 7. pii: S0304-3940(15)30023-9. doi: 10.1016/j.neulet.2015.07.005. [Epub ahead of print]
Aldecoa I, Navarro-Otano J, Stefanova N, Sprenger F, Seppi K, Poewe W, Cuatrecasas M, Valldeoriola F, Gelpi E, Tolosa E.
We aimed to compare immunoreactivity patterns of four different anti-α-syn antibodies in surgical specimens of the gastrointestinal tract of Parkinson disease and control cases. Surgical specimens from stomach, small and large bowel of 6 PD cases and 12 controls were studied. Primary antibodies: anti-α-syn clone KM51, anti-phosphorylated α-syn Ser129, anti-α-syn clone 15G7 and anti-nitrated α-syn505. We found different immunoreactivity patterns: a) coarse, Lewy-body-like aggregates labelled by the 4 antibodies and detected in 4/6 PD cases and in 1/12 controls; b) distinct punctate cytoplasmic staining of ganglion cells labelled by anti-phosphorylated-α-syn and detected in 3/6 PD cases and 3/12 controls; c) fine diffuse, synaptic-type staining of neural structures labelled by anti-α-syn-15G7 and anti-nitrated-α-syn505 and detected in all subjects. We conclude that different specific and non-specific immunoreactivity patterns are detected in surgical specimens of gastrointestinal tract when using different anti-α-syn antibodies, as they recognize different epitopes and states of alpha-synuclein protein. Coarse aggregates in neural structures seem to be the most promising marker for the diagnosis of Lewy-body parkinsonism when evaluating abnormal α-syn in the gastrointestinal tract.
Friday, 10 July 2015
Environ Health Perspect. 2015 Jul 7. [Epub ahead of print]
Ritz B, Lee PC, Hansen J, Funch Lassen C, Ketzel M, Sørensen M, Raaschou-Nielsen O.
Very little is currently known about air pollutants' adverse effects on neurodegenerative diseases even though recent studies have linked particulate exposures to brain pathologies associated with Parkinson's and Alzheimer's disease. Here we investigate long-term exposure to traffic-related air pollution and Parkinson's disease.
In a case-control study of 1,696 Parkinson's disease (PD) patients identified from Danish hospital registries and diagnosed 1996-2009 and 1,800 population controls matched by gender and year of birth we assessed long-term traffic-related air pollutant exposures (NO2) from a dispersion model, using residential addresses from 1971 to the date of diagnosis or first cardinal symptom for cases and the corresponding index date for their matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with logistic regression adjusting for matching factors and potential confounders.
We found ambient air pollution from traffic sources to be associated with risk of PD, with a 9% higher risk (95% CI: 3, 16.0%) per interquartile range increase (2.97 μg/m3) in modeled NO2. For participants living for 20 years or more in the capital city odds ratios were larger (OR= 1.21; 95% CI: 1.11, 1.31) than in provincial towns (OR=1.10; 95% CI: 0.97, 1.26), while there was no association among rural residents.
Our findings raise concerns about potential effects of air pollution from traffic and other sources on the risk of PD, particularly in populations with high or increasing exposures.
Thursday, 9 July 2015
Increased oligomerization and phosphorylation of α-synuclein are associated with decreased activity of glucocerebrosidase and protein phosphatase 2A in aging monkey brains
I don't post many basic science articles and even fewer animal studies, but I do feel this is important. The interplay between GCase and oligomeric alpha-syn may be very important for the molecular basis of Parkinson's... Targeting therapies against GCase may be relevant to GBA associated-Parkinson's and idiopathic Parkinson's...
Neurobiol Aging. 2015 Jun 11. pii: S0197-4580(15)00315-2. doi: 10.1016/j.neurobiolaging.2015.06.004. [Epub ahead of print]
Liu G, Chen M, Mi N, Yang W, Li X, Wang P, Yin N, Li Y, Yue F, Chan P, Yu S.
Aging is associated with an increased risk for Parkinson's disease and dementia with Lewy bodies, in which α-synuclein (α-syn) oligomerization plays key pathogenic roles. Here, we show that oligomeric α-syn levels increase with age in the brain of cynomolgus monkeys and are accompanied by a decrease in the expression and activity of glucocerebrosidase (GCase), a lysosomal enzyme whose dysfunction is linked to accumulation of oligomeric α-syn. Besides, levels of α-syn phosphorylated at serine 129 (pS129 α-syn), a modification that promotes α-syn oligomerization also increase with age in the brain and is associated with a reduction in the activity of protein phosphatase 2A (PP2A), an enzyme that facilitates α-syn dephosphorylation. The inverse relationship between levels of oligomeric α-syn and pS129 α-syn and activity of GCase and PP2A was more evident in brain regions susceptible to neurodegeneration (i.e., the striatum and hippocampus) than those that are less vulnerable (i.e., cerebellum and occipital cortex). In vitro experiments showed that GCase activity was more potently inhibited by oligomeric than by monomeric α-syn in the lysosome-enriched fractions isolated from brain tissues and cultured neuronal cells. Inhibition of GCase activity induced an elevation of oligomeric α-syn levels, which was shown to increase pS129 α-syn levels and reduce PP2A activity in cultured neuronal cells. The alterations in oligomeric and pS129 α-syns and their association with GCase and PP2A in aging brains may explain the vulnerability of certain brain regions to neurodegeneration in Parkinson's disease and dementia with Lewy bodies.
Wednesday, 8 July 2015
Further support to suggest that exercise has effects beyond just keeping you fit in PD.
This is a small study in subjects without dementia. It was well conducted - randomised and single blinded (investigators but not patients). At baseline, the treatment groups were similar, which suggests an even distribution of measured and unmeasured confounding factors. The effects are clinically meaningful and statistically significant despite the modest sample size... very interesting!
Mov Disord. 2015 Jul 6. doi: 10.1002/mds.26291. [Epub ahead of print]
David FJ, Robichaud JA, Leurgans SE, Poon C, Kohrt WM, Goldman JG, Comella CL, Vaillancourt DE, Corcos DM.
This article reports on the findings of the effect of two structured exercise interventions on secondary cognitive outcomes that were gathered as part of the Progressive Resistance Exercise Training in Parkinson's disease (PD) randomized, controlled trial.
This study was a prospective, parallel-group, single-center trial. Fifty-one nondemented patients with mild-to-moderate PD were randomly assigned either to modified Fitness Counts (mFC) or to Progressive Resistance Exercise Training (PRET) and were followed for 24 months. Cognitive outcomes were the Digit Span, Stroop, and Brief Test of Attention (BTA).
Eighteen patients in mFC and 20 patients in PRET completed the trial. At 12 and at 24 months, no differences between groups were observed. At 12 months, relative to baseline, mFC improved on the Digit Span (estimated change: 0.3; interquartile range: 0, 0.7; P = 0.04) and Stroop (0.3; 0, 0.6; P = 0.04), and PRET improved only on the Digit Span (0.7; 0.3, 1; P < 0.01). At 24 months, relative to baseline, mFC improved on the Digit Span (0.7; 0.3, 1.7; P < 0.01) and Stroop (0.3; 0.1, 0.5; P = 0.03), whereas PRET improved on the Digit Span (0.5; 0.2, 0.8; P < 0.01), Stroop (0.2; -0.1, 0.6; P = 0.048), and BTA (0.3; 0, 0.8; P = 0.048). No neurological or cognitive adverse events were observed.
This study provides class IV level of evidence that 24 months of PRET or mFC may improve attention and working memory in nondemented patients with mild-to-moderate Parkinson's disease.
Tuesday, 7 July 2015
CSF based biomarkers are already being used in the Alzheimer's setting and this study suggests how they might be more widely used for other neurodegenerative disorders associated with cognitive decline...
Brain. 2015 Jun 30. pii: awv181. [Epub ahead of print]
Skillbäck T, Farahmand BY, Rosén C, Mattsson N, Nägga K, Kilander L, Religa D, Wimo A, Winblad B, Schott JM, Blennow K, Eriksdotter M, Zetterberg H.
Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-β1-42 and high levels of total tau and phosphorylated tau is typical of Alzheimer's disease. However, several neurodegenerative disorders may overlap with Alzheimer's disease both in regards to clinical symptoms and neuropathology. In a uniquely large cohort of dementia patients, we examined the associations of cerebrospinal fluid biomarkers for Alzheimer's disease molecular pathology with clinical dementia diagnoses and disease severity. We cross-referenced the Swedish Dementia Registry with the clinical laboratory database at the Sahlgrenska University Hospital. The final data set consisted of 5676 unique subjects with a clinical dementia diagnosis and a complete set of measurements for cerebrospinal fluid amyloid-β1-42, total tau and phosphorylated tau. In cluster analysis, disregarding clinical diagnosis, the optimal natural separation of this data set was into two clusters, with the majority of patients with early onset Alzheimer's disease (75%) and late onset Alzheimer's disease (73%) assigned to one cluster and the patients with vascular dementia (91%), frontotemporal dementia (94%), Parkinson's disease dementia (94%) and dementia with Lewy bodies (87%) to the other cluster. Frontotemporal dementia had the highest cerebrospinal fluid levels of amyloid-β1-42 and the lowest levels of total tau and phosphorylated tau. The highest levels of total tau and phosphorylated tau and the lowest levels of amyloid-β1-42 and amyloid-β1-42:phosphorylated tau ratios were found in Alzheimer's disease. Low amyloid-β1-42, high total tau and high phosphorylated tau correlated with low Mini-Mental State Examination scores in Alzheimer's disease. In Parkinson's disease dementia and vascular dementia low cerebrospinal fluid amyloid-β1-42 was associated with low Mini-Mental State Examination score. In the vascular dementia, frontotemporal dementia, dementia with Lewy bodies and Parkinson's disease dementia groups 53%, 34%, 67% and 53% of the subjects, respectively had abnormal amyloid-β1-42 levels, 41%, 41%, 28% and 28% had abnormal total tau levels, and 29%, 28%, 25% and 19% had abnormal phosphorylated tau levels. Cerebrospinal fluid biomarkers were strongly associated with specific clinical dementia diagnoses with Alzheimer's disease and frontotemporal dementia showing the greatest difference in biomarker levels. In addition, cerebrospinal fluid amyloid-β1-42, total tau, phosphorylated tau and the amyloid-β1-42:phosphorylated tau ratio all correlated with poor cognitive performance in Alzheimer's disease, as did cerebrospinal fluid amyloid-β1-42 in Parkinson's disease dementia and vascular dementia. The results support the use of cerebrospinal fluid biomarkers to differentiate between dementias in clinical practice, and to estimate disease severity.
Monday, 6 July 2015
Perhaps expected results... parkinsonian patients not infrequently have problems with these types of task...
Int Psychogeriatr. 2015 Jul 3:1-12. [Epub ahead of print]
Tan LP, Herrmann N, Mainland BJ, Shulman K.
Studies have shown the clock-drawing test (CDT) to be a useful screening test that differentiates between normal, elderly populations, and those diagnosed with dementia. However, the results of studies which have looked at the utility of the CDT to help differentiate Alzheimer's disease (AD) from other dementias have been conflicting. The purpose of this study was to explore the utility of the CDT in discriminating between patients with AD and other types of dementia.
A review was conducted using MEDLINE, PsycINFO, and Embase. Search terms included clock drawing or CLOX and dementia or Parkinson's Disease or AD or dementia with Lewy bodies (DLB) or vascular dementia (VaD).
Twenty studies were included. In most of the studies, no significant differences were found in quantitative CDT scores between AD and VaD, DLB, and Parkinson's disease dementia (PDD) patients. However, frontotemporal dementia (FTD) patients consistently scored higher on the CDT than AD patients. Qualitative analyses of errors differentiated AD from other types of dementia.
Overall, the CDT score may be useful in distinguishing between AD and FTD patients, but shows limited value in differentiating between AD and VaD, DLB, and PDD. Qualitative analysis of the type of CDT errors may be a useful adjunct in the differential diagnosis of the types of dementias.
Sunday, 5 July 2015
Interesting report. The problem with all of these things is the heterogeneity in the clinical picture...further support for the need for biomarkers...
Neurology. 2015 Jul 2. pii: 10.1212/WNL.0000000000001807. [Epub ahead of print]
Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, Wszolek ZK, Langston JW, Dickson DW.
To determine ways to improve diagnostic accuracy of multiple system atrophy (MSA), we assessed the diagnostic process in patients who came to autopsy with antemortem diagnosis of MSA by comparing clinical and pathologic features between those who proved to have MSA and those who did not. We focus on likely explanations for misdiagnosis.
This is a retrospective review of 134 consecutive patients with an antemortem clinical diagnosis of MSA who came to autopsy with neuropathologic evaluation of the brain. Of the 134 patients, 125 had adequate medical records for review. Clinical and pathologic features were compared between patients with autopsy-confirmed MSA and those with other pathologic diagnoses, including dementia with Lewy bodies (DLB), Parkinson disease (PD), and progressive supranuclear palsy (PSP).
Of the 134 patients with clinically diagnosed MSA, 83 (62%) had the correct diagnosis at autopsy. Pathologically confirmed DLB was the most common misdiagnosis, followed by PSP and PD. Despite meeting pathologic criteria for intermediate to high likelihood of DLB, several patients with DLB did not have dementia and none had significant Alzheimer-type pathology. Autonomic failure was the leading cause of misdiagnosis in DLB and PD, and cerebellar ataxia was the leading cause of misdiagnosis in PSP.
The diagnostic accuracy for MSA was suboptimal in this autopsy study. Pathologically confirmed DLB, PD, and PSP were the most common diseases to masquerade as MSA. This has significant implications not only for patient care, but also for research studies in MSA cases that do not have pathologic confirmation.
Friday, 3 July 2015
These are really important data that shape our understanding particularly of GBA-associated PD... I am particularly interested in the results for 'benign' GBA variants as opposed to disease associated mutations. Moreover the fact that lower G-case activity is seen in PD non-carriers does (as the authors point out) make it an exciting therapeutic target!...
Brain. 2015 Jun 27. pii: awv179. [Epub ahead of print]
Alcalay RN, Levy OA, Waters CC, Fahn S, Ford B, Kuo SH, Mazzoni P, Pauciulo MW, Nichols WC, Gan-Or Z, Rouleau GA, Chung WK, Wolf P, Oliva P, Keutzer J, Marder K, Zhang X.
Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 µmol/l/h versus 7.88 µmol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 µmol/l/h versus 11.93 µmol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 µmol/l/h, versus 12.11 µmol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 µmol/l/h versus 11.93 µmol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's disease. The association of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase function contributes to the pathogenesis of Parkinson's disease. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Taken together, these data suggest that glucocerebrosidase enzymatic activity could be a modifiable therapeutic target.
Thursday, 2 July 2015
The diagnostic value of dopamine transporter imaging and olfactory testing in patients with parkinsonian syndromes
The problem with this study is the use of the B-SIT which is far more restricted than the UPSIT (12 items versus 40). Previous studies have shown comparable diagnostic accuracy between UPSIT and DaTSCAN, although one might perhaps expect imaging to perform better than objective smell testing. One needs to consider the costs here... UPSIT $25 and DaTSCAN over $1000. In my opinion both have a place in the clinical and research setting, and agree that in combination predictive value is likely to maximal...
J Neurol. 2015 Jun 30. [Epub ahead of print]
Georgiopoulos C, Davidsson A, Engström M, Larsson EM, Zachrisson H, Dizdar N.
The aim of the study was to compare the efficacy of olfactory testing and presynaptic dopamine imaging in diagnosing Parkinson's disease (PD) and atypical parkinsonian syndromes (APS); to evaluate if the combination of these two diagnostic tools can improve their diagnostic value. A prospective investigation of 24 PD patients, 16 APS patients and 15 patients with non-parkinsonian syndromes was performed during an 18-month period. Single photon emission computed tomography with the presynaptic radioligand 123I-FP-CIT (DaTSCAN®) and olfactory testing with the Brief 12-item Smell Identification Test (B-SIT) were performed in all patients. DaTSCAN was analysed semi-quantitatively, by calculating two different striatal uptake ratios, and visually according to a predefined ranking scale. B-SIT score was significantly lower for PD patients, but not significantly different between APS and non-parkinsonism. The visual assessment of DaTSCAN had higher sensitivity, specificity and diagnostic accuracy compared to olfactory testing. Most PD patients (75 %) had visually predominant dopamine depletion in putamen, while most APS patients (56 %) had visually severe dopamine depletion both in putamen and in caudate nucleus. The combination of DaTSCAN and B-SIT led to a higher rate of correctly classified patients. Olfactory testing can distinguish PD from non-parkinsonism, but not PD from APS or APS from non-parkinsonism. DaTSCAN is more efficient than olfactory testing and can be valuable in differentiating PD from APS. However, combining olfactory testing and DaTSCAN imaging has a higher predictive value than these two methods separately.
Body Mass Index and Risk of Parkinson's Disease: A Dose-Response Meta-Analysis of Prospective Studies
No association with BMI and risk of Parkinson's overall, but confounding factors may be having a big role in this...
PLoS One. 2015 Jun 29;10(6):e0131778. doi: 10.1371/journal.pone.0131778. eCollection 2015.
Wang YL, Wang YT, Li JF, Zhang YZ, Yin HL, Han B.
A number of epidemiologic studies examining the relationship between body mass index (BMI) and the future occurrence of Parkinson's disease (PD) reported largely inconsistent findings. We conducted a dose-response meta-analysis of prospective studies to clarify this association.
Eligible prospective studies were identified by a search of PubMed and by checking the references of related publications. The generalized least squares trend estimation was employed to compute study-specific relative risks (RR) and 95% confidence intervals (CI) for an increase in BMI of 5 kg/m2, and the random-effects model was used to compute summary RR and 95% CI.
A total of 10 prospective studies were included in the final analysis. An increase in BMI of 5 kg/m2 was not associated with PD risk, with a summary RR of 1.00 (95% CI = 0.89-1.12). Results of subgroup analysis found similar results except for a week positive association in studies that adjusted for alcohol consumption (RR = 1.13, 95% CI = 0.99-1.29), and a week inverse association in studies that did not (RR = 0.90, 95% CI = 0.78-1.04). In a separate meta-analysis, no significant association between overweight (25 kg/m2 ≤ BMI ≤29.9 kg/m2), obesity (BMI≥30 kg/m2) or excess weight (BMI≥25 kg/m2) and PD risk was observed.
This meta-analysis does not support the notion that higher BMI materially increases PD risk. However, a week positive BMI-PD association that may be masked by confounders still cannot be excluded, and future prospective studies with a good control for potential confounding factors are needed.
This is a study of potentially vital importance to our understand of the prodrome(s) of PD. Here the authors show that people with mild park...
What motivates Parkinson's disease patients to enter clinical trials? Valadas A, Coelho M, Mestre T et al. Parkinsonism Relat Disord....
Motor and non-motor correlates of olfactory dysfunction in Parkinson's disease. Berendse HW , Roos DS , Raijmakers P , Doty RL . J...