Thiazolidinediones and Parkinson Disease: A Cohort Study

No disease-modifying effect of thiazolidinediones compared with sulphonylureas in this large cohort study...

Am J Epidemiol. 2015 Oct 22. pii: kwv109. [Epub ahead of print]

Connolly JG, Bykov K, Gagne JJ.

http://aje.oxfordjournals.org/content/early/2015/10/22/aje.kwv109.abstract

Abstract

Thiazolidinediones, a class of medications indicated for the treatment of type 2 diabetes mellitus, reduce inflammation and have been shown to provide a therapeutic benefit in animal models of Parkinson disease. We examined the association between treatment with thiazolidinediones and the onset of Parkinson disease in older individuals. We performed a cohort study of 29,397 Medicare patients enrolled in state pharmaceutical benefits programs who initiated treatment with thiazolidinediones or sulfonylureas during the years 1997 through 2005 and had no prior diagnosis of Parkinson disease. New users of thiazolidinediones were propensity score matched to new users of sulfonylureas and followed to determine whether they were diagnosed with Parkinson disease. We used Cox proportional hazards models to compare time to diagnosis of Parkinson disease in the propensity score-matched populations. To assess the association with duration of use, we performed several analyses that required longer continuous use of medications. In the primary analysis, thiazolidinedione users had a hazard ratio for a diagnosis of Parkinson disease of 1.09 (95% confidence interval: 0.71, 1.66) when compared with sulfonylurea users. Increasing the duration-of-use requirements to 10 months did not substantially change the association; the hazard ratios ranged from 1.00 (95% confidence interval: 0.49, 2.05) to 1.17 (95% confidence interval: 0.60, 2.25). Thiazolidinedione use was not associated with a longer time to diagnosis of Parkinson disease than was sulfonylurea use, regardless of duration of exposure.

My Sky News Interview on 'Sniffing Out Parkinson's disease' on Thursday 22nd October

Woman who can 'smell out Parkinson's disease' inspires new study

When researchers talk about smell and Parkinson's disease, they are often talking about the fact that loss of a sense of smell can be one of the earliest features of the disease. Indeed, at the PREDICT-PD project we are smell loss as one of a number of early clues that might help predict the onset of Parkinson's disease.

However, lately there has been talk of the possibility of 'sniffing out' Parkinson's disease, inspired by a woman who appears to be able to detect the condition, simply through body odour.

Joy Milne, whose husband, Les, recently died after living with Parkinson's for 20 years, recalls how she noticed a very subtle change in her husband's aroma starting about 6 years before he first developed the condition.

Mrs Milne, 65, from Perth, Scotland, was attending a talk by Dr Tilo Kunath, a researcher at the University of Edinburgh, where she mentioned this to Dr Kunath, who became interested in testing her ability to detect the disease through smell alone.

Dr Kunath set up a pilot study where he had Mrs Milne smell the t-shirts of 6 people without Parkinson's disease and 6 people with the disease. Mrs Milne correctly classified 11 out of the 12 participants, though the researchers note that she was adamant the final subject who she identified "incorrectly" did have Parkinson's. This participant was diagnosed with the disease 8 months later. Amazingly, not only could Joy identify the disease, but she could also predict it before it had manifested clinically.

Parkinson's UK are now funding researchers at Manchester, Edinburgh and London to study around 200 people with and without Parkinson's.

The experts will analyse skin swabs to identify small molecules that are found in people with Parkinson's, with the hope of creating a diagnostic test.

The team will also use "human detectors" - people with exceptional smelling abilities - to back up the study.

The idea of using smell (or the analysis of 'volatile organic compunds') to identify diseases, including Parkinson's, is not new. In Feburary this year, Professor Hossam Haick and his team at the Technion – Israel Institute of Technology published results which showed their technique to be 85% accurate at detecting Parkinson's disease using participants' breath.

I think this is a great example of how patient interest in Parkinson's disease research can help inspire a new scientific ventures. The Parkinson's disease research community is lucky to have a patient population who are particularly active in and engaged with research, and this is a relationship we should cherish!

Tracking Parkinson's: Study Design and Baseline Patient Data

The first data from the Tracking Parkinson's study... this is a great study and I am looking forward to seeing more data from this initiative...

J Parkinsons Dis. 2015 Oct 20. [Epub ahead of print]

Malek N, Swallow DM, Grosset KA, Lawton MA, Marrinan SL, Lehn AC, Bresner C, Bajaj N, Barker RA, Ben-Shlomo Y, Burn DJ, Foltynie T, Hardy J, Morris HR, Williams NM, Wood N, G Grosset D.

BACKGROUND:

There is wide variation in the phenotypic expression of Parkinson's disease (PD), which is driven by both genetic and epidemiological influences.

OBJECTIVES:

To define and explain variation in the clinical phenotype of PD, in relation to genotypic variation.

METHODS:

Tracking Parkinson's is a multicentre prospective longitudinal epidemiologic and biomarker study of PD. Patients attending specialist clinics in the United Kingdom with recent onset (<3.5 years) and young onset (diagnosed <50 years of age) PD were enrolled. Motor, non-motor and quality of life assessments were performed using validated scales. Cases are followed up 6 monthly up to 4.5 years for recent onset PD, and up to 1 year for young onset PD. We present here baseline clinical data from this large and demographically representative cohort.

RESULTS:

2247 PD cases were recruited (1987 recent onset, 260 young onset). Recent onset cases had a mean (standard deviation, SD) age of 67.6 years (9.3) at study entry, 65.7% males, with disease duration 1.3 years (0.9), MDS-UPDRS 3 scores 22.9 (12.3), LEDD 295 mg/day (211) and PDQ-8 score 5.9 (4.8). Young onset cases were 53.5 years old (7.8) at study entry, 66.9% male, with disease duration 10.2 years (6.7), MDS-UPDRS 3 scores 27.4 (15.3), LEDD 926 mg/day (567) and PDQ-8 score 11.6 (6.1).

CONCLUSIONS:

We have established a large clinical PD cohort, consisting of young onset and recent onset cases, which is designed to evaluate variation in clinical expression, in relation to genetic influences, and which offers a platform for future imaging and biomarker research.

The Concept of Prodromal Parkinson's Disease

A nice review from friends and colleagues in Austria....

J Parkinsons Dis. 2015 Oct 17. [Epub ahead of print]

Mahlknecht P, Seppi K, Poewe W.

Abstract

Parkinson's disease (PD) is currently clinically defined by a set of cardinal motor features centred on the presence of bradykinesia and at least one additional motor symptom out of tremor, rigidity or postural instability. However, converging evidence from clinical, neuropathological, and imaging research suggests initiation of PD-specific pathology prior to appearance of these classical motor signs. This latent phase of neurodegeneration in PD is of particular relevance in relation to the development of disease-modifying or neuroprotective therapies which would require intervention at the earliest stages of disease. A key challenge in PD research, therefore, is to identify and validate markers for the preclinical and prodromal stages of the illness. Currently, several nonmotor symptoms have been associated with an increased risk to develop PD in otherwise healthy individuals and ongoing research is aimed at validating a variety of candidate PD biomarkers based on imaging, genetic, proteomic, or metabolomic signatures, supplemented by work on tissue markers accessible to minimally invasive biopsies. The definition of diagnostic criteria for prodromal PD will have to include combinations of markers which could define target populations and influence outcomes of future disease modification trials.

Brain-gut-microbiota axis in Parkinson's disease

This is one of the hot topics in PD currently, with a couple of studies reported thus far but no clear culprit to date... expect much more on this in the coming years...

World J Gastroenterol. 2015 Oct 7;21(37):10609-20. doi: 10.3748/wjg.v21.i37.10609.

Mulak A, Bonaz B.

Parkinson's disease (PD) is characterized by alpha-synucleinopathy that affects all levels of the brain-gut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological, neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding. Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gut-microbiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.

Parkinson's disease: A risk factor for osteoporosis

An update on bone health and PD that draws on some of our previous work and the work of others....this is an important but under-recognised issue for patients...

Joint Bone Spine. 2015 Oct 6. pii: S1297-319X(15)00156-6. doi: 10.1016/j.jbspin.2015.03.009. [Epub ahead of print]

Malochet-Guinamand S, Durif F, Thomas T.

Abstract

Parkinson's disease is the most common neurodegenerative disease after Alzheimer's disease. On the long term, it may be complicated by various musculoskeletal problems, such as osteoporotic fractures, that have significant socioeconomic consequences. Indeed, patients suffering from Parkinson's disease have a higher fracture risk, particularly hip fracture risk, than other subjects of the same age because of both a higher risk of falls and lower bone mineral density. Bone loss in Parkinson's disease may be associated with the severity and duration of the disease. We review here the different suspected mechanisms of accelerated bone loss in Parkinson's disease, amongst which weight loss and reduced mobility appear to play key roles. Antiparkinsonian drugs, particularly levodopa, may also be associated with decreased bone mineral density as a result of hyperhomocysteinaemia. We discuss the role of other nutritional deficiencies, such as vitamin B12, folate or vitamin K. In conclusion, it seems necessary to screen for and treat osteoporosis in this at-risk population, while actions to prevent falls are still disappointing. A better understanding of the factors explaining bone loss in this population would help implementing preventive actions.

Genetic variability in ABCB1, occupational pesticide exposure, and Parkinson's disease

Further evidence that genetic and environmental risk should not be considered in independent silos. Genetic variability likely contributes to the effect that environmental exposures have on PD causation. Some gene mutations are of course sufficient to cause PD, whereas there is limited evidence that any environmental exposure in isolation can cause PD...

Environ Res. 2015 Oct 9;143(Pt A):98-106. doi: 10.1016/j.envres.2015.08.022. [Epub ahead of print]

Narayan S, Sinsheimer JS, Paul KC, Liew Z, Cockburn M, Bronstein JM, Ritz B.

BACKGROUND:

Studies suggested that variants in the ABCB1 gene encoding P-glycoprotein, a xenobiotic transporter, may increase susceptibility to pesticide exposures linked to Parkinson's Disease (PD) risk.

OBJECTIVES:

To investigate the joint impact of two ABCB1 polymorphisms and pesticide exposures on PD risk.

METHODS:

In a population-based case control study, we genotyped ABCB1 gene variants at rs1045642 (c.3435C/T) and rs2032582 (c.2677G/T/A) and assessed occupational exposures to organochlorine (OC) and organophosphorus (OP) pesticides based on self-reported occupational use and record-based ambient workplace exposures for 282 PD cases and 514 controls of European ancestry. We identified active ingredients in self-reported occupational use pesticides from a California database and estimated ambient workplace exposures between 1974 and 1999 employing a geographic information system together with records for state pesticide and land use. With unconditional logistic regression, we estimated marginal and joint contributions for occupational pesticide exposures and ABCB1 variants in PD.

RESULTS:

For occupationally exposed carriers of homozygous ABCB1 variant genotypes, we estimated odds ratios of 1.89 [95% confidence interval (CI): (0.87, 4.07)] to 3.71 [95% CI: (1.96, 7.02)], with the highest odds ratios estimated for occupationally exposed carriers of homozygous ABCB1 variant genotypes at both SNPs; but we found no multiplicative scale interactions.

CONCLUSIONS:

This study lends support to a previous report that commonly used pesticides, specifically OCs and OPs, and variant ABCB1 genotypes at two polymorphic sites jointly increase risk of PD.

'Biomarkers' in body fluids might be able to help researchers determine whether a new treatment for PD is effective at slowing the disease process. Pioglitazone is a drug usually used to treat diabetes, which was recently trialled in patients with PD to see if it might help slow disease progression. Unfortunately, the trial did not show any effect on disease progression judged by traditional 'clinical' markers.

In this new study, researchers have used blood-based biomarkers of inflammation and oxidative DNA damage to assess whether pioglitazone might be having a neuroprotective effect that was not clinically detectable in the original clinical trial. Pioglitazone did not alter the biomarker levels, suggesting protect against oxidative stress and inflammation in PD.

This is an interesting example of how body fluid biomarkers can be used to assess whether a potentially neuroprotective agent might be working as expected. However, the blood biomarkers used here are not particularly well validated -- they may not be very specific to PD and their precise relationship with disease progression remains undetermined. Of note, for the patients in this study, baseline levels of the biomarkers and changes in the biomarkers were not associated with rate of disease progression. As a result, it is still difficult to draw conclusions about pioglitazone's efficacy as a disease-modifying drug, despite the negative results of this study.

Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects.

Simon DK, Simuni T, Elm J, Clark-Matott J, Graebner AK, Baker L, Dunlop SR, Emborg M, Kamp C, Morgan JC, Ross GW, Sharma S, Ravina B

Abstract: Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson’s disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD.

DOI: 10.3233/JPD-150666

Journal: Journal of Parkinson's Disease, 

Published 3 October 2015

Simon DK, Simuni T, Elm J, Clark-Matott J, Graebner AK, Baker L, Dunlop SR, Emborg M, Kamp C, Morgan JC, Ross GW, Sharma S, & Ravina B (2015). Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects. Journal of Parkinson's disease PMID: 26444095

Minor hallucinations occur in drug-naive Parkinson's disease patients, even from the premotor phase

Further characterising the cognitive/psychiatric phenomena which are now not only recognised to be present in late stages of parkinson's disease but often even before motor symptoms.  42% of patients in this newly diagnosed cohort of PD patients reported minor hallucinations in the preceeding 3 months - significantly less than healthy control subjects, with a third of these occurring before motor symptoms. 

Follow up of these patients was interesting: L-dopa equivalent doses did not differ between PD patients with and without hallucinations in an average of 4.4 years follow up. Only 3 of 21 patients went on to develop dementia over this time course. So, no evidence here to suggest that these patients experience a more severe disease course. 

A correlation with REM sleep behaviour disorder may well be significant; further characterisation of this group prospectively, from premotor to end stage disease is certainly worthwhile.

Mov Disord. 2015 Sep 26. doi: 10.1002/mds.26432. [Epub ahead of print] Pagonabarraga J, Martinez-Horta S, Fernandez de Bobadilla R, et al.

http://www.ncbi.nlm.nih.gov/pubmed/26408291

OBJECTIVES:

The description of minor hallucinatory phenomena (presence, passage hallucinations) has widened the spectrum of psychosis in Parkinson's disease (PD). Minor hallucinatory phenomena seem to antedate the development of more severe hallucinations. Early detection of minor hallucinations may be useful for screening patients with more severe endophenotypes. Motivated by the observation of "de novo," drug-naive PD patients reporting minor hallucinations, we aimed to prospectively identify "de novo" untreated PD patients experiencing hallucinatory phenomena, and to compare their clinico-demographic characteristics with those of untreated PD patients without hallucinations and healthy controls.

METHODS:

Screening and description of psychosis was assessed by the Movement Disorders Society Unified Parkinson's Disease Rating Scale-Part I and a structured interview covering all types of psychotic phenomena reported in PD. Clinical, neuropsychological, and demographic data of PD patients with and without psychotic phenomena were compared with those of age- and education-matched healthy controls.

RESULTS:

Fifty drug-naive, "de novo" PD patients and 100 controls were prospectively included. Minor hallucinations were experienced in 42% (21 of 50) PD patients and 5% controls (P < 0.0001). Coexistence of passage and presence hallucinations was the most common finding. Unexpectedly, 33.3% of patients with minor hallucinations manifested these as a pre-motor symptom, starting 7 months to 8 years before first parkinsonian motor symptoms. The presence of minor hallucinations was significantly associated with presence of rapid eye movement sleep behavior disorder.

CONCLUSIONS:

In this first study to prospectively analyze the frequency of minor hallucinatory phenomena in incident, untreated PD patients, hallucinations appeared as a frequent early non-motor symptom that may even predate the onset of parkinsonism. © 2015 International Parkinson and Movement Disorder Society.

GBA mutations are associated with Rapid Eye Movement Sleep Behavior Disorder

Interesting to see these data published... I saw them presented at MDS Congress in San Diego in June 2015... supports the notion that GBA gives rise to a more unpleasant form of PD of which RBD is part. Also supports a role for the 'debated' GBA variants in PD such as E326K and backs up observations by Beavan et al, made earlier this year...

Ann Clin Transl Neurol. 2015 Sep;2(9):941-5. doi: 10.1002/acn3.228. Epub 2015 Jul 31.

Gan-Or Z, Mirelman A, Postuma RB, Arnulf I, Bar-Shira A, Dauvilliers Y, Desautels A, Gagnon JF, Leblond CS, Frauscher B, Alcalay RN, Saunders-Pullman R, Bressman SB, Marder K, Monaca C, Högl B, Orr-Urtreger A, Dion PA, Montplaisir JY, Giladi N, Rouleau GA.

http://onlinelibrary.wiley.com/doi/10.1002/acn3.228/abstract;jsessionid=02B24FF15ED9CB0A8D74F808B6F79C74.f03t02

Abstract

Rapid eye movement sleep behavior disorder and GBA mutations are both associated with Parkinson's disease. The GBA gene was sequenced in idiopathic rapid eye movement sleep behavior disorder patients (n = 265), and compared to controls (n = 2240). Rapid eye movement sleep behavior disorder questionnaire was performed in an independent Parkinson's disease cohort (n = 120). GBA mutations carriers had an OR of 6.24 (10.2% in patients vs. 1.8% in controls, P < 0.0001) for rapid eye movement sleep behavior disorder, and among Parkinson's disease patients, the OR for mutation carriers to have probable rapid eye movement sleep behavior disorder was 3.13 (P = 0.039). These results demonstrate that rapid eye movement sleep behavior disorder is associated with GBA mutations, and that combining genetic and prodromal data may assist in identifying individuals susceptible to Parkinson's disease.