Monday, 29 June 2015

Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial

Disappointing results reported from this phase II RCT of pioglitazone in early PD... further trials of this drug not recommended....

Lancet Neurol. 2015 Jun 23. pii: S1474-4422(15)00144-1. doi: 10.1016/S1474-4422(15)00144-1. [Epub ahead of print]
NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators.


BACKGROUND:
A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial.

METHODS:
Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov, number NCT01280123.

FINDINGS:
210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55-6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17-7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35-8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was -1·83 (80% CI -3·56 to -0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was -1·12 (80% CI -2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions.

INTERPRETATION:
These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended.

FUNDING:

National Institute of Neurological Disorders and Stroke.

Friday, 26 June 2015

Risk of Premotor Symptoms in Patients with Newly Diagnosed PD: A Nationwide, Population-Based, Case-Control Study in Taiwan

I like this study although there are some limitations. The diagnostic criteria for PD are a little loose, as are the criteria for RBD. But the effect size estimates for other prodromal features appear pretty standard (adding credence to the overall findings), and whilst the interval between onset of non-motor features and diagnosis is conservative, it is perhaps to be expected given the methods of data collection. Some people will reject the effect size estimate for RBD and say it is too small... this may be true... or it may reflect the fact these subjects were diagnosed with PD rather than parkinsonism....


PLoS One. 2015 Jun 24;10(6):e0130282. doi: 10.1371/journal.pone.0130282.
Wu YH, Liao YC, Chen YH, Chang MH, Lin CH.

BACKGROUND:
To evaluate the risk of premotor symptoms, namely rapid eye movement behavior disorder (RBD), constipation, and depression among patients with newly diagnosed Parkinson disease (PD).

METHODS:
A total of 705 PD patients and 2,820 control subjects were selected from the Taiwan National Health Insurance Research Database. Patients were traced back for a maximum of 14 years to determine the diagnoses of RBD, depression, and constipation. Logistic regression analysis was used to identify risk of premotor symptoms for PD. Moreover, subgroup analyses were performed by dividing the patients into a middle-age onset group (≤ 64 years) and an old-age onset group (≥ 65 years). The associations between these premotor symptoms and age of PD onset were further examined.

RESULTS:
An association was found between a history of premotor symptoms and newly diagnosed PD in which a high occurrence of premotor symptoms was identified in PD patients as compared to selected controls (4.3% vs. 1.2% for RBD, 40.4% vs. 24.0% for constipation, and 13.0% vs. 5.1% for depression). The strength of this association remained statistically significant after adjustment for potential confounders (3.69 fold risk for RBD, 2.36 for constipation, and 2.82 for depression, all p < 0.0001). The average interval between premotor symptoms and PD ranged from 4.5 to 6.2 years. RBD and depression carried higher risks for PD in the middle-age onset group than in the old-age onset group (7.20- vs. 2.24-fold risk for RBD, 6.06 vs. 1.40 for depression).

CONCLUSION:

The prevalence of premotor symptoms was higher among the PD patients than in the controls. Premotor symptoms appeared to be associated with a higher risk for PD in subjects with an earlier age of onset.

Thursday, 25 June 2015

Can we use peripheral tissue biopsies to diagnose Parkinson's disease? A review of the literature.

Timely review as the hunt for peripheral tissue diagnosis of PD has been going on for some time now. We don't yet know enough about what the tissue of healthy controls looks like and until we do it is difficult to draw conclusions about what it looks like in disease. This is made all the more complicated by the fact that some 'healthy' people may go on to be diagnosed with Parkinson's but may have pathological changes in these regions that long precede the diagnosis...


Eur J Neurol. 2015 Jun 23. doi: 10.1111/ene.12753. [Epub ahead of print]
Schneider SA, Boettner M, Alexoudi A, Zorenkov D, Deuschl G, Wedel T.

Abstract

Phosphorylated α-synuclein (phosαSYN) containing inclusions in neurons (Lewy bodies, LB) and nerve terminals (Lewy neurites, LN), the pathological hallmark of Parkinson's disease (PD), are not confined to the central nervous system, but have also been reported in peripheral tissues. However, the usefulness of αSYN/phosαSYN detection in tissues accessible to biopsies as a reliable biomarker for prodromal PD remains unclear. A systematic review of studies using biopsies of skin, olfactory and gastrointestinal (GI) tissues was conducted to evaluate the sensitivity and specificity of both αSYN and phosαSYN staining in PD patients. Data analysis was hampered by the diversity of the methods used, e.g. choice of biopsy sites, tissue processing, staining protocols and evaluation of the findings. Tissue obtained from GI tract/salivary glands (13 post-mortem, 13 in vivo studies) yielded the highest overall sensitivity and specificity compared to skin (three post-mortem, eight in vivo studies) and olfactory mucosa/bulb (six post-mortem studies, one in vivo study). In contrast to phosαSYN, αSYN was more consistently detectable in peripheral tissues of healthy controls. GI tract/salivary glands appear to be the most promising candidate tissue for peripheral biopsy-taking. phosαSYN is considered as the marker of choice to delineate pathological aggregates from normal αSYN regularly found in peripheral neural tissues. However, the sensitivity and specificity of phosαSYN are not yet acceptable for using phosαSYN as a reliable peripheral biomarker for PD in clinical routine. Further refinement regarding the interpretation of the peripheral αSYN/phosαSYN burden and the phenotypical definition of peripheral LB/LN is needed to optimize screening methods for prodromal PD.

Dopa-responsive dystonia-clinical and genetic heterogeneity

A hot topic right now and keenly debated at the recent MDS Congress in San Diego... These are a rare and fascinating group of conditions...Some of which may be risk factor for degenerative parkinsonism later in life.


Nat Rev Neurol. 2015 Jun 23. doi: 10.1038/nrneurol.2015.86. [Epub ahead of print]
Wijemanne S, Jankovic J.

Abstract

Dopa-responsive dystonia (DRD) encompasses a group of clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia and exhibit a robust and sustained response to levodopa treatment. Autosomal dominant GTP cyclohydrolase 1 deficiency, also known as Segawa disease, is the most common and best-characterized condition that manifests as DRD, but a similar presentation can be seen with genetic abnormalities that lead to deficiencies in tyrosine hydroxylase, sepiapterin reductase or other enzymes that are involved in the biosynthesis of dopamine. In rare cases, DRD can result from conditions that do not affect the biosynthesis of dopamine; single case reports have shown that DRD can be a manifestation of hereditary spastic paraplegia type 11, spinocerebellar ataxia type 3 and ataxia telangiectasia. This heterogeneity of conditions that underlie DRD frequently leads to misdiagnosis, which delays the appropriate treatment with levodopa. Correct diagnosis at an early stage requires use of the appropriate diagnostic tests, which include a levodopa trial, genetic testing (including whole-exome sequencing), cerebrospinal fluid neurotransmitter analysis, the phenylalanine loading test, and enzyme activity measurements. The selection of tests for use depends on the clinical presentation and level of complexity. This Review presents the common and rarer causes of DRD and their clinical features, and considers the most appropriate approaches to ensure early diagnosis and treatment.

Thursday, 18 June 2015

Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

This is much lower than I expected and previous studies have shown significantly higher age-dependent penetrance in other ethnic groups. Understanding the factors that dictate penetrance in LRRK2 carriers is a interesting area for further research...

Neurology. 2015 Jun 10. pii: 10.1212/WNL.0000000000001708. [Epub ahead of print]
Marder K, Wang Y, Alcalay RN, Mejia-Santana H, Tang MX, Lee A, Raymond D, Mirelman A, Saunders-Pullman R, Clark L, Ozelius L, Orr-Urtreger A, Giladi N, Bressman S; LRRK2 Ashkenazi Jewish Consortium.

OBJECTIVE:
Estimates of the penetrance of LRRK2 G2019S vary widely (24%-100%), reflective of differences in ascertainment, age, sex, ethnic group, and genetic and environmental modifiers.

METHODS:
The kin-cohort method was used to predict penetrance in 2,270 relatives of 474 Ashkenazi Jewish (AJ) Parkinson disease (PD) probands in the Michael J. Fox LRRK2 AJ Consortium in New York and Tel Aviv, Israel. Patients with PD were genotyped for the LRRK2 G2019S mutation and at least 7 founder GBA mutations. GBA mutation carriers were excluded. A validated family history interview, including age at onset of PD and current age or age at death for each first-degree relative, was administered. Neurologic examination and LRRK2 genotype of relatives were included when available.

RESULTS:
Risk of PD in relatives predicted to carry an LRRK2 G2019S mutation was 0.26 (95% confidence interval [CI] 0.18-0.36) to age 80 years, and was almost 3-fold higher than in relatives predicted to be noncarriers (hazard ratio [HR] 2.89, 95% CI 1.73-4.55, p < 0.001). The risk among predicted G2019S carrier male relatives (0.22, 95% CI 0.10-0.37) was similar to predicted carrier female relatives (0.29, 95% CI 0.18-0.40; HR male to female: 0.74, 95% CI 0.27-1.63, p = 0.44). In contrast, predicted noncarrier male relatives had a higher risk (0.15, 95% CI 0.11-0.20) than predicted noncarrier female relatives (0.07, 95% CI 0.04-0.10; HR male to female: 2.40, 95% CI 1.50-4.15, p < 0.001).

CONCLUSION:

Penetrance of LRRK2 G2019S in AJ is only 26% and lower than reported in other ethnic groups. Further study of the genetic and environmental risk factors that influence G2019S penetrance is warranted.

Wednesday, 17 June 2015

Transcranial sonography of the substantia nigra and its correlation with DAT-SPECT in the diagnosis of Parkinson's disease

Agree to some extent... the problem that remains with TCS is the huge subjectivity. If there is clear hyperechogenicity then it really jumps out at you, but there are a lot of unclear cases. The lack of correlation with dopamine transporter imaging is consistent with what other studies have found....

Parkinsonism Relat Disord. 2015 Jun 3. pii: S1353-8020(15)00242-4. doi: 10.1016/j.parkreldis.2015.05.024. [Epub ahead of print]
Li DH, Zhang LY, Hu YY, Jiang XF, Zhou HY, Yang Q, Kang WY, Liu J, Chen SD.

INTRODUCTIONS:
Transcranial sonography (TCS) of the substantia nigra is a new and promising method to diagnose Parkinson's disease (PD) but its effectiveness is controversial.

METHODS:
All 55 PD patients involved in the study underwent single photon emission computed tomography (SPECT) imaging using the labeled dopamine transporter radiotracer 99mTc-TRODAT-1 to assess nigrostriatal dopaminergic function. The echogenicity of the substantia nigra was measured by TCS in all patients who received DAT-SPECT scanning. Finally, statistical analysis was carried out to determine the diagnostic accuracy of TCS as well as its correlation with 99mTc-TRODAT-1 SPECT, its positive predictive value (PPV), and negative predictive value (NPV).

RESULTS:
Contralateral striatal 99mTc-TRODAT-1 uptake was significantly reduced compared to ipsilateral striatal uptake, and had a negative correlation with UPDRS-Ⅲ(r = -0.334, p = 0.013), disease duration (r = -0.393, p = 0.003) and H-Y stage (r = -0.330, p = 0.014). After TCS measurement, the contralateral SN echogenic area was similar to the ipsilateral SN echogenic area (27.77 ± 13.19 vs 25.98 ± 11.94 mm2, p = 0.402, n = 24). No correlation was identified between TCS and UPDRS-Ⅲ (r = 0.383, p = 0.065), disease duration (r = 0.371, p = 0.075) or H-Y stage (r = 0.259, p = 0.222). The sensitivity and specificity of SN TCS for the diagnosis of PD were calculated as 64.70% and 60% according to DAT-SPECT, respectively, while the positive predictive value and negative predictive value was calculated as 91.67% and 20%, respectively.

CONCLUSIONS:

Compared to DAT-SPECT, TCS is a non-radioactive and convenient procedure to perform. In our investigation, TCS had no correlation with DAT-SPECT. However, the high positive predictive value of TCS highlights its possible utility as a routine diagnostic test.

Tuesday, 16 June 2015

New Clinical Subtypes of Parkinson Disease and Their Longitudinal Progression: A Prospective Cohort Comparison With Other Phenotypes

This is potentially helpful. There are clearly different 'types' of Parkinson's and a number of groups are working hard to sub-classify accurately beyond previous classifications based primarily on motor features (such as tremulous versus akinetic rigid types). My feeling is that greater numbers of patients are required to accurately define these sub-categories but it is true that the more aggressive forms are likely to feature orthostatic hypotension, RBD and cognitive impairment...

JAMA Neurol. 2015 Jun 15. doi: 10.1001/jamaneurol.2015.0703. [Epub ahead of print]
Fereshtehnejad SM, Romenets SR, Anang JB, Latreille V, Gagnon JF, Postuma RB.

IMPORTANCE:
There is increasing evidence that Parkinson disease (PD) is heterogeneous in its clinical presentation and prognosis. Defining subtypes of PD is needed to better understand underlying mechanisms, predict disease course, and eventually design more efficient personalized management strategies.

OBJECTIVES:
To identify clinical subtypes of PD, compare the prognosis and progression rate between PD phenotypes, and compare the ability to predict prognosis in our subtypes and those from previously published clustering solutions.

DESIGN, SETTING, AND PARTICIPANTS:
Prospective cohort study. The cohorts were from 2 movement disorders clinics in Montreal, Quebec, Canada (patients were enrolled during the period from 2005 to 2013). A total of 113 patients with idiopathic PD were enrolled. A comprehensive spectrum of motor and nonmotor features (motor severity, motor complications, motor subtypes, quantitative motor tests, autonomic and psychiatric manifestations, olfaction, color vision, sleep parameters, and neurocognitive testing) were assessed at baseline. After a mean follow-up time of 4.5 years, 76 patients were reassessed. In addition to reanalysis of baseline variables, a global composite outcome was created by merging standardized scores for motor symptoms, motor signs, cognitive function, and other nonmotor manifestations.

MAIN OUTCOMES AND MEASURES:
Changes in the quintiles of the global composite outcome and its components were compared between different subtypes.

RESULTS:
The best cluster solution found was based on orthostatic hypotension, mild cognitive impairment, rapid eye movement sleep behavior disorder (RBD), depression, anxiety, and Unified Parkinson's Disease Rating Scale Part II and Part III scores at baseline. Three subtypes were defined as mainly motor/slow progression, diffuse/malignant, and intermediate. Despite similar age and disease duration, patients with the diffuse/malignant phenotype were more likely to have mild cognitive impairment, orthostatic hypotension, and RBD at baseline, and at prospective follow-up, they showed a more rapid progression in cognition (odds ratio [OR], 8.7 [95% CI, 4.0-18.7]; P < .001), other nonmotor symptoms (OR, 10.0 [95% CI, 4.3-23.2]; P < .001), motor signs (OR, 4.1 [95% CI, 1.8-9.1]; P = .001), motor symptoms (OR, 2.9 [95% CI, 1.3-6.2]; P < .01), and the global composite outcome (OR, 8.0 [95% CI, 3.7-17.7]; P < .001).

CONCLUSIONS AND RELEVANCE:

It is recommended to screen patients with PD for mild cognitive impairment, orthostatic hypotension, and RBD even at baseline visits. These nonmotor features identify a diffuse/malignant subgroup of patients with PD for whom the most rapid progression rate could be expected.

Monday, 15 June 2015

Natural history of multiple system atrophy in the USA: a prospective cohort study

Really important study that throws up some surprising results... I think one needs to be a little wary with cases that a diagnosed clinically and pathological confirmation is so important... certainly some patients with MSA-P have very prolonged disease durations compared with MSA-C...

Lancet Neurol. 2015 May 26. pii: S1474-4422(15)00058-7. doi: 10.1016/S1474-4422(15)00058-7. [Epub ahead of print]
Low PA, Reich SG, Jankovic J, Shults CW, Stern MB, Novak P, Tanner CM, Gilman S, Marshall FJ, Wooten F, Racette B, Chelimsky T, Singer W, Sletten DM, Sandroni P, Mandrekar J.


BACKGROUND:
Multiple system atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first prospective natural history study of multiple system atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis.

METHODS:
We recruited participants with probable multiple system atrophy-of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)-at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables.

FINDINGS:
We recruited 175 participants. Mean age at study entry was 63·4 years (SD 8·6). Median survival from symptom onset was 9·8 years (95% CI 8·8-10·7) and median survival from enrolment was 1·8 years (0·9-2·7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8·0 years, 95% CI 6·5-9·5 vs 10·3 years, 9·3-11·4; p=0·021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25·2 (SD 8·08) versus 24·6 (8·34; p=0·835); mean UMSARS II 26·4 (8·8) versus 25·4 (10·5; p=0·764); COMPASS-select 43·5 (18·7) versus 42·8 (19·6; p=0·835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest.
INTERPRETATION:
Probable multiple system atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis.
FUNDING:

US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation.

Sunday, 14 June 2015

Vagotomy and subsequent risk of Parkinson's disease

Novel approach and interesting...however virtually all the confidence intervals cross the point of unity even if the trend fits with a protective effect...

Ann Neurol. 2015 May 29. doi: 10.1002/ana.24448. [Epub ahead of print]
Svensson E, Horváth-Puhó E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sørensen HT.


OBJECTIVES:
Parkinson's disease (PD) may be caused by an enteric neurotropic pathogen entering the brain through the vagal nerve, a process that may take over 20 years. We investigated the risk of PD in patients who underwent vagotomy, and hypothesized that truncal vagotomy is associated with a protective effect, while super-selective vagotomy has a minor effect.

METHODS:
We constructed cohorts of all patients in Denmark who underwent vagotomy during 1977-1995 and a matched general population cohort, by linking Danish registries. We used Cox regression to compute hazard ratios (HRs) for PD and corresponding 95% confidence intervals [CIs], adjusting for potential confounders.

RESULTS:
Risk of PD was decreased in patients who underwent truncal [HR = 0.85, 95% CI= 0.56-1.27; follow-up of >20 years: HR = 0.58, 95% CI: 0.28-1.20] compared to super-selective vagotomy. Risk of PD was also decreased following truncal vagotomy when compared to the general population cohort [overall adjusted HR = 0.85, 95% CI 0.63-1.14; follow-up >20 years, adjusted HR = 0.53 [95% CI: 0.28-0.99]. In patients who underwent super-selective vagotomy, risk of PD was similar to the general population [HR = 1.09, 95% CI: 0.84-1.43; follow-up of >20 years: HR = 1.16, 95% CI: 0.80-1.70]. The statistical precision of the risk estimates was limited. Results were consistent after external adjustment for unmeasured confounding by smoking.

INTERPRETATION:

Full truncal vagotomy is associated with a decreased risk for subsequent PD, suggesting that the vagal nerve may be critically involved in the pathogenesis of PD. 


Saturday, 13 June 2015

Risk of Parkinson's disease following anxiety disorders: a nationwide population-based cohort study

Consistent with the results of previous observational studies and a dose dependent effect as well...

Eur J Neurol. 2015 May 29. doi: 10.1111/ene.12740. [Epub ahead of print]
Lin CH, Lin JW, Liu YC, Chang CH, Wu RM.

BACKGROUND AND PURPOSE:
Anxiety is potentially a pre-motor symptom of Parkinson's disease (PD). Our aim was to investigate the association between anxiety and subsequent PD risk in a population-based sample.

METHODS:
A total of 174 776 participants, who were free of prior PD, dementia and stroke, were enrolled from Taiwan National Health Insurance Research Database between 1 January 2005 and 31 December 2005. The association between anxiety at the beginning of the study and the incidence of PD was examined using a Cox regression model. Information regarding comorbidities, especially depression, and concomitant medication use was adjusted in the proportional hazards models.

RESULTS:
Over an average follow-up of 5.5 years, 2258 incident PD cases were diagnosed. After adjusting for age, sex, comorbidities and concomitant medication use, patients with anxiety were more likely to develop PD than subjects without anxiety [adjusted hazard ratio (HR) 1.38; 95% confidence interval (CI) 1.26-1.51]. Anxiety severity was dose-dependently associated with increased likelihood of PD: crude HR 1.27 (95% CI 1.11-1.44) for mild anxiety, 1.35 (95% CI 1.19-1.53) for moderate anxiety and 2.36 (95% CI 2.13-2.62) for severe anxiety (P < 0.0001). Results were similar after adjustment for age, sex, comorbid depression and other PD risk factors, and in the sensitivity analyses excluding participants with comorbid depression or with a PD diagnosis <3 years after anxiety diagnosis, and controlling for Charlson's scores.

CONCLUSIONS:

The likelihood of developing PD was greater amongst patients with anxiety than patients without anxiety, and the severity of anxiety correlated with risk of PD.

Friday, 12 June 2015

Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial

Study results from the Neurturin trial...

Ann Neurol. 2015 Jun 10. doi: 10.1002/ana.24436. [Epub ahead of print]
Warren Olanow C, Bartus RT, Baumann TL, Factor S, Boulis N, Stacy M, Turner DA, Marks W, Larson P, Starr PA, Jankovic J, Simpson R, Watts R, Guthrie B, Poston K, Henderson JM, Stern M, Baltuch G, Goetz CG, Herzog C, Kordower JH, Alterman R, Lozano AM, Lang AE.

OBJECTIVE:
A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra.

METHODS:
We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 1011 vector genomes) and putamen (1.0 × 1012 vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state.

RESULTS:
Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 ± 9.92; sham, -5.2 ± 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin.

INTERPRETATION:

AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin. 

Thursday, 11 June 2015

α-Synuclein strains cause distinct synucleinopathies after local and systemic administration

Evidence to support the seeding, propagating potential of alpha-synuclein, as well as its neuro-toxic potential...

Nature. 2015 Jun 10. doi: 10.1038/nature14547. [Epub ahead of print]
Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M, Van den Haute C, Melki R, Baekelandt V.


Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton α-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial α-synuclein (α-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal α-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of α-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that α-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined α-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that α-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that α-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct α-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.

Quantitative home-based assessment of Parkinson's symptoms: The SENSE-PARK feasibility and usability study

Feasibility of the SENSE-PARK system... aiming to improve objective measurement of PD symptoms....

BMC Neurol. 2015 Jun 10;15:89. doi: 10.1186/s12883-015-0343-z.
Ferreira JJ, Godinho C, Santos AT, Domingos J, Abreu D, Lobo R, Gonçalves N, Barra M, Larsen F, Fagerbakke Ø, Akeren I, Wangen H, Serrano JA, Weber P, Thoms A, Meckler S, Sollinger S, van Uem J, Hobert MA, Maier KS, Matthew H, Isaacs T, Duffen J, Graessner H, Maetzler W.

BACKGROUND:
Currently, assessment of symptoms associated with Parkinson's disease is mainly performed in the clinic. However, these assessments have limitations because they provide only a snapshot of the condition.

METHODS:
The feasibility and usability of an objective, continuous and relatively unobtrusive system (SENSE-PARK System), which consists of wearable sensors (three worn during the day and one worn at night), a smartphone-based App, a balance board and computer software, was tested 24/7 over 12 weeks in a study including 22 PD patients. During the first four weeks of the study, patients did not get feedback about their performance, during the last eight weeks they did. The study included seven clinical visits with standardized interviews, and regular phone contact. The primary outcome was the number of drop-outs during the study. As secondary outcomes, the Post-Study System Usability Questionnaire (PSSUQ), score and information obtained from the standardized interviews were used to evaluate the usability of the system.

RESULTS:
All patients completed the study. The participants rated the usability of the SENSE-PARK System with a mean score of 2.67 (±0.49) on the PSSUQ. The interviews revealed that most participants liked using the system and appreciated that it signaled changes in their health condition.

CONCLUSIONS:

This 12 week controlled study demonstrates that the acceptance level of PD patients using the SENSE-PARK System as a home-based 24/7 assessment is very good. Particular emphasis should be given to a user-friendly design. Motivation to wear such a system can be increased by providing direct feedback about the individual health condition.

Monday, 1 June 2015

Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson's disease from multiple system atrophy

This is an amazing result and the clearest evidence yet that a skin may yield useful biomarkers for PD. Important to show this in larger numbers that have post-mortem confirmation of diagnosis...

Brain. 2015 May 27. pii: awv138. [Epub ahead of print]
Zange L, Noack C, Hahn K, Stenzel W, Lipp A.

Abstract

Deposition of phosphorylated SNCA (also known as α-synuclein) in cutaneous nerve fibres has been shown pre- and post-mortem in Parkinson's disease. Thus far, no pre-mortem studies investigating the presence of phosphorylated SNCA in skin sympathetic nerve fibres of multiple system atrophy, another synucleinopathy, have been conducted. In this in vivo study, skin from the ventral forearm of 10 patients with multiple system atrophy and 10 with Parkinson's disease, together with six control subjects with essential tremor, were examined by immunohistochemistry. Phosphorylated SNCA deposits in skin sympathetic nerve fibres and dermal nerve fibre density were assessed. All patients with Parkinson's disease expressed phosphorylated SNCA in sympathetic skin nerve fibres, correlating with an age-independent denervation of autonomic skin elements. In contrast, no phosphorylated SNCA was found in autonomic skin nerve fibres of patients with multiple system atrophy and essential tremor control subjects. These findings support that phosphorylated SNCA deposition is causative for nerve fibre degeneration in Parkinson's disease. Moreover, pre-mortem investigation of phosphorylated SNCA in cutaneous nerve fibres may prove a relevant and easily conductible diagnostic procedure to differentiate Parkinson's disease from multiple system atrophy.