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.

Parkinson's Disease Subtypes in the Oxford Parkinson Disease Centre (OPDC) Discovery Cohort

Interesting cluster analysis giving rise to sub-types of PD... saw some of these data in an early form last year... the groups make sense clinically and you 'recognise' the patients to which they refer... would be interesting to see longitudinal data on these groups...

J Parkinsons Dis. 2015 Jun 1;5(2):269-79. doi: 10.3233/JPD-140523.

Lawton M, Baig F, Rolinski M, Ruffman C, Nithi K, May MT, Ben-Shlomo Y, Hu MT.

http://content.iospress.com/articles/journal-of-parkinsons-disease/jpd140523

BACKGROUND:

Within Parkinson's there is a spectrum of clinical features at presentation which may represent sub-types of the disease. However there is no widely accepted consensus of how best to group patients.

OBJECTIVE:

Use a data-driven approach to unravel any heterogeneity in the Parkinson's phenotype in a well-characterised, population-based incidence cohort.

METHODS:

769 consecutive patients, with mean disease duration of 1.3 years, were assessed using a broad range of motor, cognitive and non-motor metrics. Multiple imputation was carried out using the chained equations approach to deal with missing data. We used an exploratory and then a confirmatory factor analysis to determine suitable domains to include within our cluster analysis. K-means cluster analysis of the factor scores and all the variables not loading into a factor was used to determine phenotypic subgroups.

RESULTS:

Our factor analysis found three important factors that were characterised by: psychological well-being features; non-tremor motor features, such as posture and rigidity; and cognitive features. Our subsequent five cluster model identified groups characterised by (1) mild motor and non-motor disease (25.4%), (2) poor posture and cognition (23.3%), (3) severe tremor (20.8%), (4) poor psychological well-being, RBD and sleep (18.9%), and (5) severe motor and non-motor disease with poor psychological well-being (11.7%).

CONCLUSION:

Our approach identified several Parkinson's phenotypic sub-groups driven by largely dopaminergic-resistant features (RBD, impaired cognition and posture, poor psychological well-being) that, in addition to dopaminergic-responsive motor features may be important for studying the aetiology, progression, and medication response of early Parkinson's.

Gender Differences in Age-Related Striatal Dopamine Depletion in Parkinson's Disease

Another DATSCAN study, this time looking at gender differences in DAT binding, which have been shown plenty of times. The authors discuss the potential role of oestrogen...

J Mov Disord. 2015 Sep;8(3):130-5. doi: 10.14802/jmd.15031. Epub 2015 Sep 10.

Lee JJ, Ham JH, Lee PH, Sohn YH.

http://e-jmd.org/journal/view.php?doi=10.14802/jmd.15031

OBJECTIVE:

Gender differences are a well-known clinical characteristic of Parkinson's disease (PD). In-vivo imaging studies demonstrated that women have greater striatal dopamine transporter (DAT) activity than do men, both in the normal population and in PD patients. We hypothesize that women exhibit more rapid aging-related striatal DAT reduction than do men, as the potential neuroprotective effect of estrogen wanes with age.

METHODS:

This study included 307 de novo PD patients (152 men and 155 women) who underwent DAT scans for an initial diagnostic work-up. Gender differences in age-related DAT decline were assessed in striatal sub-regions using linear regression analysis.

RESULTS:

Female patients exhibited greater DAT activity compared with male patients in all striatal sub-regions. The linear regression analysis revealed that age-related DAT decline was greater in the anterior and posterior caudate, and the anterior putamen in women compared with men; we did not observe this difference in other sub-regions.

CONCLUSIONS:

This study demonstrated the presence of gender differences in age-related DAT decline in striatal sub-regions, particularly in the antero-dorsal striatum, in patients with PD, presumably due to aging-related decrease in estrogen. Because this difference was not observed in the sensorimotor striatum, this finding also suggests that women may not have a greater capacity to tolerate PD pathogenesis than do men.

Nigro-caudate dopaminergic deafferentation: a marker of REM sleep behavior disorder?

Interesting result... observing differential reduction in binding according to presence/absence of RBD. The worsening in putaminal binding ratio from RBD to PD without RBD to PD with RBD was expected... the caudate binding differences were not...

Neurobiol Aging. 2015 Sep 3. pii: S0197-4580(15)00442-X. doi: 10.1016/j.neurobiolaging.2015.08.025. [Epub ahead of print]

Arnaldi D, De Carli F, Picco A, Ferrara M, Accardo J, Bossert I, Famà F, Girtler N, Morbelli S, Sambuceti G, Nobili F.

http://www.sciencedirect.com/science/article/pii/S019745801500442X

Abstract

Forty-nine consecutive, drug naïve outpatients with de novo Parkinson's disease (PD) and 12 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) underwent clinical examination and dopamine transporter single photon emission computed tomography with [123I]-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane as a biomarker of nigro-striatal function. PD patients were grouped into rapid eye movement sleep behavior disorder (RBD) negative (PD-RBD-) and RBD positive (PD-RBD+). Repeated measures and univariate analysis of variance were used to compare dopaminergic and clinical impairment among groups. The variations of dopamine transporter-single photon emission computed tomography specific binding ratios (SBR) as a function of group belonging were significantly different (p = 0.0013) at caudate with respect to putamen level. Indeed, putamen SBR progressively decreased from iRBD to PD-RBD- and PD-RBD+ groups while caudate SBR were higher in PD-RBD- group than in PD-RBD+ and even than in iRBD group. Motor impairment was more severe in PD patients with RBD than in those without RBD. Our data suggest that a more severe nigro-caudate dopaminergic deafferentation is related to RBD, both in its idiopathic form and in PD patients.

Cognitive impairment in Parkinson's disease and dementia with Lewy bodies

Cognitive impairment is a common outcome in PD and mild cognitive impairment may be seen in some patients at the point of diagnosis. Better biomarkers and neuroprotective strategies to prevent descent into dementia are essential...

Parkinsonism Relat Disord. 2015 Sep 21. pii: S1353-8020(15)00425-3. doi: 10.1016/j.parkreldis.2015.09.034. [Epub ahead of print]

Aarsland D.

http://www.sciencedirect.com/science/article/pii/S1353802015004253

Abstract

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) share clinical and pathological similarities. The defining features are motor parkinsonism and cognitive impairment, often accompanied by visual hallucinations, fluctuating consciousness, autonomic and sleep disturbances, and a number of other non-motor symptoms. Mild cognitive impairment (MCI) can be identified in 15% of PD patients at time of diagnosis, and may even precede motor symptoms. MCI usually progresses further, and dementia is a common endpoint. Cognitive impairment is usually the initial symptom of DLB, and the disease course is severe. A variety of biomarkers can assist in the diagnosis and prognosis of PD and DLB, including structural and functional imaging, cerebrospinal fluid, and EEG. Compared to the many treatments available for motor symptoms, relatively few systematic studies exist to guide the treatment of cognitive impairment in PD, and even less in DLB. However, there is good evidence for cholinesterase inhibitors in both DLB and PD with dementia, and some indications that memantine is helpful. Emerging evidence suggest that physical exercise and cognitive training are also effective, as are some reports of various brain stimulation techniques. Disease-modifying agents that delay the rate of cognitive decline in PD and DLB are urgently needed.

The relevance of pre-motor symptoms in Parkinson's disease

New review on early non-motor features of PD...

Expert Rev Neurother. 2015 Oct;15(10):1205-17. doi: 10.1586/14737175.2015.1083423. Epub 2015 Sep 1.

Visanji N, Marras C.

Abstract

Parkinson's disease (PD) has a wide range of non-motor symptoms including; constipation, sleep disturbance, deficits in vision and olfaction, mood disorders and cardiac autonomic dysfunction. Several of these non-motor symptoms can manifest prior to the onset of motor symptoms. Recognizing these pre-motor symptoms may enable early diagnosis of PD. Currently, no single pre-motor symptom is able to predict the development of PD with 100% sensitivity or specificity. Ongoing studies in several independent at-risk cohorts should reveal the potential of combinations of pre-motor symptoms and multi-stage screening strategies to identify individuals at increased risk of PD. PD progression may be governed by a prion-like spread of a-syn throughout the nervous system. Identifying individuals at the earliest stage will likely be critical to preventing the pathological progression of PD, highlighting the relevance of pre-motor symptoms in the future treatment of the disease.

A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease

de novo mutations identified through unbiased exome sequencing approach...

Hum Mol Genet. 2015 Sep 11. pii: ddv376. [Epub ahead of print]

Kun-Rodrigues C, Ganos C, Guerreiro R, Schneider SA, Schulte C, Lesage S, Darwent L, Holmans P, Singleton A; International Parkinson's Disease Genomics Consortium (IPDGC), Bhatia K, Bras J.

http://hmg.oxfordjournals.org/content/early/2015/09/11/hmg.ddv376.long

Abstract

Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical Parkinson's disease to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1,200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein-protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes.