PREDICT-PD aligns with the highest priorities for clinical research in PD

Prioritized Research Recommendations from NINDS Parkinson's Disease 2014

Ann Neurol. 2014 Aug 28. doi: 10.1002/ana.24261. [Epub ahead of print]

Sieber BA, Landis S, Koroshetz W, Bateman R, Siderowf A, Galpern WR, Dunlop J, Finkbeiner S, Sutherland M, Wang H, Lee VM, Orr HT, Gwinn K, Ludwig K, Taylor A, Torborg C, Montine TJ; for the Parkinson's Disease 2014: Advancing Research, Improving Lives Conference Organizing Committee.

Abstract

Parkinson's disease (PD) is a serious and rapidly growing public health problem. Growing understanding of PD has unveiled substantial medical and biological complexity including preclinical disease, motor and non-motor symptoms, multi-organ involvement, co-morbidity, and an array of potential molecular drivers and mechanisms of disease that likely vary among patients. The National Institute of Neurological Disorders and Stroke (NINDS) convened Parkinson's Disease 2014: Advancing Research, Improving Lives to build consensus on PD research priorities. Our thirty-one recommendations form a foundation for precision medicine that will bring individual clarity to the medical and biological complexity of PD. 

http://onlinelibrary.wiley.com/doi/10.1002/ana.24261/abstract

Phenotypic variability of PINK1 expression: 12 Years' clinical follow-up of two Italian families

Interesting observations about PINK1 Parkinson's... raises important questions about why these patients exhibit different features to those with Parkin-related disease...

Mov Disord. 2014 Aug 27. doi: 10.1002/mds.25994. [Epub ahead of print]

Ricciardi L, Petrucci S, Guidubaldi A, Ialongo T, Serra L, Ferraris A, Spanò B, Bozzali M, Valente EM, Bentivoglio AR.

BACKGROUND:

Mutations in the PINK1 gene are the second most frequent cause of autosomal recessive early-onset parkinsonism.

METHODS:

We evaluated five affected PINK1 homozygous and 14 heterozygous mutation carriers from two large Italian families over a 12-year follow-up period. Motor, nonmotor, cognitive, psychiatric, and behavioral profiles were systematically assessed. Four homozygotes and eight heterozygotes underwent magnetic resonance imaging.

RESULTS:

All homozygotes showed a mild progression of motor signs and a persistent excellent response to levodopa. All but one patient complained of nonmotor symptoms and sleep impairment. Three presented impulse control disorders and two anxiety and apathy. All obtained abnormal scores at Montreal Cognitive Assessment (MoCA) and in tests sensitive to frontal functions; one presented a global cognitive impairment. Three heterozygotes showed motor signs and were diagnosed as possibly affected. They had nonmotor symptoms and cognitive impairment, and two of them showed mild bilateral temporal atrophy. Five unaffected heterozygotes reported abnormal scores at MoCA and low performances at tests sensitive to frontal functions.

CONCLUSION:

We expanded the phenotypic profile of PINK1-related parkinsonism, including psychiatric and cognitive features as part of clinical presentation.

And now back to PD with this excellent video about visual hallucinations

This video was prepared by Professor Joseph Friedman MD at Brown University

Momentary departure from PD to raise awareness for another awful neurodegenerative disease

MND Ice Bucket Challenge

Glucocerebrosidase depletion enhances cell-to-cell transmission of ​α-synuclein

Eun-Jin Bae,

Na-Young Yang,

Miyoung Song,

Cheol Soon Lee,

Jun Sung Lee,

Byung Chul Jung,

He-Jin Lee,

Seokjoong Kim,

Eliezer Masliah,

Sergio Pablo Sardi

& Seung-Jae Lee

• Nature Communications
   
  5,
   
  Article number:
   
  4755
   
  doi:10.1038/ncomms5755

Received

 

22 February 2014 

Accepted

 

18 July 2014 

Published

 

26 August 2014

Deposition of ​α-synuclein aggregates occurs widely in the central and peripheral nervous systems in Parkinson’s disease (PD). Although recent evidence has suggested that cell-to-cell transmission of ​α-synuclein aggregates is associated with the progression of PD, the mechanism by which ​α-synuclein aggregates spread remains undefined. Here, we show that ​α-synuclein aggregates are transmitted from cell to cell through a cycle involving uptake of external aggregates, co-aggregation with endogenous ​α-synuclein and exocytosis of the co-aggregates. Moreover, we find that ​glucocerebrosidase depletion, which has previously been strongly associated with PD and increased cognitive impairment, promotes propagation of ​α-synuclein aggregates. These studies define how ​α-synuclein aggregates spread among neuronal cells and may provide an explanation for how ​glucocerebrosidase mutations increase the risk of developing PD and other synucleinopathies.

Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders

1. Sharmilee Gnanapavan, MD, PhD, 
2. Harald Hegen, MD, PhD, 
3. Michael Khalil, MD, PhD, 
4. Bernhard Hemmer, MD, PhD,
5. Diego Franciotta, MD, 
6. Steve Hughes, MD, 
7. Rogier Hintzen, MD, PhD, 
8. Andreas Jeromin, PhD, 
9. Eva Havrdova, MD, PhD, 
10. Hayrettin Tumani, MD, PhD, 
11. Antonio Bertolotto, MD, PhD, 
12. Manuel Comabella, MD, 
13. Jette Frederiksen, MD, DMSc, 
14. José C. Álvarez-Cermeño, MD, PhD, 
15. Luisa Villar, PhD, 
16. Daniela Galimberti, MD, PhD, 
17. Kjell-Morten Myhr, MD, PhD, 
18. Irena Dujmovic, MD, PhD, 
19. Franz Fazekas, MD, 
20. Carolina Ionete, MD, PhD, 
21. Til Menge, MD, PhD, 
22. Geoffrey Keir, PhD, 
23. Florian Deisenhammer, MD, MSc, 
24. Charlotte Teunissen, PhD and 
25. Gavin Giovannoni, MBBCh, PhD

1. Published online before print August 22, 2014Neurology 

Objective: The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development.

Methods: BioMS-eu consortium, a collaborative network working toward improving the quality of biomarker research in neurologic disorders, discussed the merits of standardizing the reporting of body fluid biomarker research. A checklist of items integrating the results of other published guidances, literature, conferences, regulatory opinion, and personal expertise was created to ultimately form a structured summary guidance incorporating the key features.

Results: The summary guidance is comprised of a 10-point uniform reporting format ranging from introduction, materials and methods, through to results and discussion. Each item is discussed in detail in the guidance report.

Conclusions: To enhance the future development of body fluid biomarkers, it will be important to standardize the reporting of studies. This guideline by the BioMS-eu consortium is aimed at setting a standard for the reporting of future body fluid biomarker research studies in neurologic disorders. We anticipate that following these guidelines will help to accelerate the selection of biomarkers for clinical development.

Zolpidem and the risk of Parkinson's disease: A nationwide population-based study

J Psychiatr Res. 2014 Jul 25. pii: S0022-3956(14)00200-3. doi: 10.1016/j.jpsychires.2014.07.003. [Epub ahead of print]

Yang YW, Hsieh TF, Yu CH, Huang YS, Lee CC, Tsai TH.

BACKGROUND:

This nationwide population-based study investigated the risk of Parkinson's disease (PD) after zolpidem use in patients with sleep disturbance using the National Health Insurance Research Database (NHIRD) in Taiwan.

MATERIAL AND METHODS:

In total, 59,548 adult patients newly diagnosed with sleep disturbance and who used zolpidem were recruited as the study cohort, along with 42,171 subjects who did not use zolpidem as a comparison cohort from 2002 to 2009. Each patient was monitored for 5 years, and those who subsequently had PD were identified. A Cox proportional hazards model was used to compare the risk of PD between the study and comparison cohorts after adjusting for possible confounding risk factors.

RESULTS:

The patients who received zolpidem had a higher cumulative rate of PD than those who did not receive zolpidem during the 5-year follow-up period (1.2% vs. 0.5%, P < 0.001). The adjusted hazard ratios were 1.10 (95% CI, 0.88-1.37), 1.41 (95% CI, 1.17-1.72), and 1.27 (95% CI, 1.05-1.55) for zolpidem use with 28-90, 91-365, and more than 365 cumulative defined daily doses (cDDDs), respectively, compared to those who did not use zolpidem.

CONCLUSIONS:

Among the patients with sleep disturbance, zolpidem use increased the risk of PD after 5 years of follow-up. Further mechanistic research of zolpidem effect in PD is needed.

Presence and progression of non-motor symptoms in relation to uric acid in de novo Parkinson's disease

Eur J Neurol. 2014 Aug 7. doi: 10.1111/ene.12533. [Epub ahead of print]

Moccia M, Picillo M, Erro R, Vitale C, Longo K, Amboni M, Santangelo G, Palladino R, Capo G, Orefice G, Barone P, Pellecchia MT.

BACKGROUND AND PURPOSE:

Uric acid (UA) has been studied extensively as a valuable biomarker of Parkinson's disease (PD), but its relationship with non-motor symptoms (NMS) in de novo PD has been poorly investigated. Our aim was to evaluate the usefulness of baseline serum UA as a marker of NMS progression in newly diagnosed PD.

METHODS:

Sixty-nine newly diagnosed PD patients were enrolled. At baseline, all patients completed the NMS questionnaire (NMSQuest), and serum UA levels were measured. After 2 years, the NMSQuest was completed again and patients were categorized into four groups: NMS improvement (domain involvement at baseline but not at 2-year follow-up visit), NMS absence (domain not involved at baseline or 2-year follow-up visits), NMS presence (domain involvement both at baseline and 2-year follow-up visits) and NMS worsening (domain not involved at baseline but involved at 2-year follow-up).

RESULTS:

anova with post hoc Bonferroni correction showed that patients with NMS absence presented significantly higher UA values than patients with NMS presence with regard to the attention/memory (P = 0.023), depression/anxiety (P = 0.028) and cardiovascular domains (P = 0.002), whilst no differences were found with regard to both the NMS improvement and worsening groups. In addition, multinomial regression analysis showed that the lowest tertile of NMS progression presented higher UA levels (P = 0.023; odds ratio 0.488) compared with patients with greater NMS progression.

CONCLUSIONS:

This is the first report of a relationship between serum UA and presence/progression of multiple NMS in de novo PD, providing additional evidence of the reliability of UA as a biomarker of PD and opening new insights on PD neuroprotection.

Occupational exposure to pesticides and endotoxin and Parkinson disease in the Netherlands.

Occup Environ Med. 2014 Aug 7. pii: oemed-2014-102170. doi: 10.1136/oemed-2014-102170. [Epub ahead of print]

van der Mark M, Vermeulen R, Nijssen PC, Mulleners WM, Sas AM, van Laar T, Brouwer M, Huss A, Kromhout H.

OBJECTIVES:

Previous research has indicated that occupational exposure to pesticides and possibly airborne endotoxin may increase the risk of developing Parkinson disease (PD). We studied the associations of PD with occupational exposure to pesticides, specifically to the functional subclasses insecticides, herbicides and fungicides, and to airborne endotoxin. In addition we evaluated specific pesticides (active ingredients) previously associated with PD.

METHODS:

We used data from a hospital-based case-control study, including 444 patients with PD and 876 age and sex matched controls. Exposures to pesticides from application and re-entry work were estimated with the ALOHA+job-exposure matrix and with an exposure algorithm based on self-reported information on pesticide use. To assess exposure to specific active ingredients a crop-exposure matrix was developed. Endotoxin exposure was estimated with the DOM job-exposure matrix.

RESULTS:

The results showed almost no significant associations. However, ORs were elevated in the higher exposure categories for pesticides in general, insecticides, herbicides and fungicides, and below unity for endotoxin exposure. The analyses on specific active ingredients showed a significant association of PD risk with the fungicide benomyl.

CONCLUSIONS:

This study did not provide evidence for a relation between pesticide exposure and PD. However, the consistently elevated ORs in the higher exposure categories suggest that a positive association may exist. The possible association with the active ingredient benomyl requires follow-up in other studies. This study did not provide support for a possible association between endotoxin exposure and PD.

In vivo gastric detection of α-synuclein inclusions in Parkinson's disease.

Alpha-synuclein in the stomach... 

Mov Disord. 2014 Aug 11. doi: 10.1002/mds.25988. [Epub ahead of print]

Sánchez-Ferro A, Rábano A, Catalán MJ, Rodríguez-Valcárcel FC, Díez SF, Herreros-Rodríguez J, García-Cobos E, Alvarez-Santullano MM, López-Manzanares L, Mosqueira AJ, Desojo LV, López-Lozano JJ, López-Valdés E, Sánchez-Sánchez R, Molina-Arjona JA.

Abstract

α-Synuclein inclusions have been identified in the brain and some parts of the enteric nervous system in Parkinson's disease cases. We aimed to assess these inclusions in gastric mucosa samples from patients with symptomatic Parkinson's disease. Random biopsies were performed by gastroscopy in 28 patients with Parkinson's disease and in 29 age- and sex-matched controls. Gastroscopy was performed to start enteral levodopa (l-dopa) therapy in cases and for diagnostic purposes in controls (gastroesophageal reflux, anemia, and abdominal pain were the main indications). The clinical definition of cases and controls was made a priori. Six controls had data suggestive of "mild presymptomatic parkinsonism". Biopsy specimens were immunostained for α-synuclein. The neuropathological diagnosis was established post hoc. No differences were found in the baseline characteristics of the groups. Positive fibers for the α-synuclein protein were observed in 17 of 28 (60.7%) Parkinson's disease patients, 1 of 23 controls (4.3%), and 1 of 6 (16.7%) cases of incident "mild presymptomatic parkinsonism." Neuropathological diagnosis based on α-synuclein immunostaining showed a sensitivity of 85% (95% confidence interval [CI] 62.1-96.8), specificity of 95% (95% CI 76.2-99.9) and area under the receiver operating characteristics curve (AUC) of 0.90 (95% CI 0.80-1.00). No adverse events occurred. Detection of α-synuclein inclusions in the gastric mucosa is a useful and safe tool providing in vivo evidence of the underlying neurodegenerative peripheral involvement linked to Parkinson's disease. Further studies are warranted to determine its pathophysiological implications.

Inverse association between cancer and neurodegenerative disease: review of the epidemiologic and biological evidence

Biogerontology. 2014 Aug 12. [Epub ahead of print]

Driver JA.

Abstract

Growing evidence suggests an unusual epidemiologic association between cancer and certain neurological conditions, particularly age-related neurodegenerative diseases. Cancer survivors have a 20-50 % lower risk of developing Parkinson's and Alzheimer's disease, and patients with these neurodegenerative conditions have a substantially lower incidence of cancer. We review the epidemiologic evidence for this inverse co-morbidity and show that it is not simply an artifact of survival bias or under-diagnosis. We then review the potential biological explanations for this association, which is intimately linked to the very different nature of dividing cells and neurons. The known genetic and metabolic connections between cancer and neurodegeneration generally fall within two categories. The first includes shared genes and pathways such as Pin1 and the ubiquitin proteasome system that are dysregulated in different directions to cause one disease or the other. The second includes common pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress and DNA damage that drive both conditions, but with different cellular fates. We discuss examples of these biological links and their implications for developing new approaches to prevention and treatment of both diseases.