The mPower study, Parkinson disease mobile data collected using ResearchKit

Really exciting to see these data being released... particularly after an uplifting set of talks at UCL Partners on Friday on Tech in Health Care... the aim of these tools is to guide clinical practice and provide real world, practical solutions to augment the subjective and 'snapshot' nature of clinical consultations... looking forward to having a look through (if authorised!)...

Sci Data. 2016 Mar 3;3:160011. doi: 10.1038/sdata.2016.11.

Bot BM, Suver C, Neto EC, Kellen M, Klein A, Bare C, Doerr M, Pratap A, Wilbanks J, Dorsey ER, Friend SH, Trister AD.

http://www.nature.com/articles/sdata201611

Current measures of health and disease are often insensitive, episodic, and subjective. Further, these measures generally are not designed to provide meaningful feedback to individuals. The impact of high-resolution activity data collected from mobile phones is only beginning to be explored. Here we present data from mPower, a clinical observational study about Parkinson disease conducted purely through an iPhone app interface. The study interrogated aspects of this movement disorder through surveys and frequent sensor-based recordings from participants with and without Parkinson disease. Benefitting from large enrollment and repeated measurements on many individuals, these data may help establish baseline variability of real-world activity measurement collected via mobile phones, and ultimately may lead to quantification of the ebbs-and-flows of Parkinson symptoms. App source code for these data collection modules are available through an open source license for use in studies of other conditions. We hope that releasing data contributed by engaged research participants will seed a new community of analysts working collaboratively on understanding mobile health data to advance human health.

Alpha-synuclein as a biomarker for Parkinson's disease

Review article on the potential utility for alpha-synuclein as a biomarker of PD...

Brain Pathol. 2016 Mar 3. doi: 10.1111/bpa.12370. [Epub ahead of print]

Atik A, Stewart T, Zhang J.

http://onlinelibrary.wiley.com/doi/10.1111/bpa.12370/abstract;jsessionid=92F2F43B695BCC5377DD2170EEF6740D.f04t03

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized pathologically by the presence of α-synuclein (α-syn)-rich Lewy bodies. As clinical diagnosis of PD is challenging, misdiagnosis is common, highlighting the need for disease-specific and early stage biomarkers. Both early diagnosis of PD and adequate tracking of disease progression could significantly improve outcomes for patients, particularly in regard to existing and future disease modifying treatments. Given its critical roles in PD pathogenesis, α-syn may be useful as a biomarker of PD. The aim of this review is, therefore, to summarize the efficacy of tissue and body fluid α-syn measurements in the detection of PD as well as monitoring disease progression. In comparison to solid tissue specimens and biopsies, biofluid α-syn levels may be the most promising candidates in PD diagnosis and progression based on specificity, sensitivity and availability. Although α-syn has been tested most extensively in cerebrospinal fluid (CSF), the relatively invasive procedure for collecting CSF is not suitable in most clinical settings, leading to investigation of plasma, blood and saliva as alternatives. The exploration of combined biomarkers, along with α-syn, to improve diagnostic accuracy is also likely required.

Restless legs syndrome associated with major diseases: A systematic review and new concept

Interesting update on RLS... clearly associated with iron deficiency anaemia and kidney disease, but other disease associations may be explained (at least in part) by bias and confounding. The spectrum of causal factors that underlie RLS is wide and current clinical categorisation may fail to capture that... and may have implications on treatment...

Neurology. 2016 Mar 4. pii: 10.1212/WNL.0000000000002542. [Epub ahead of print]

Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J.

Recent publications on both the genetics and environmental factors of restless legs syndrome (RLS) defined as a clinical disorder suggest that overlapping genetic risk factors may play a role in primary (idiopathic) and secondary (symptomatic) RLS. Following a systematic literature search of RLS associated with comorbidities, we identified an increased prevalence of RLS only in iron deficiency and kidney disease. In cardiovascular disease, arterial hypertension, diabetes, migraine, and Parkinson disease, the methodology of studies was poor, but an association might be possible. There is insufficient evidence for conditions such as anemia (without iron deficiency), chronic obstructive pulmonary disease, multiple sclerosis, headache, stroke, narcolepsy, and ataxias. Based on possible gene-microenvironmental interaction, the classifications primary and secondary RLS may suggest an inappropriate causal relation. We recognize that in some conditions, treatment of the underlying disease should be achieved as far as possible to reduce or eliminate RLS symptoms. RLS might be seen as a continuous spectrum with a major genetic contribution at one end and a major environmental or comorbid disease contribution at the other.

The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder

This is amazing... it would be great to see this replicated in other RBD cohorts and in other groups thought to be at higher risk of PD... notable that alternate finger tapping also distinguished the cases from the controls!

Brain. 2016 Feb 26. pii: aww006. [Epub ahead of print]

Ehrminger M, Latimier A, Pyatigorskaya N, Garcia-Lorenzo D, Leu-Semenescu S, Vidailhet M, Lehericy S, Arnulf I.

http://brain.oxfordjournals.org/content/early/2016/02/25/brain.aww006.long

Idiopathic rapid eye movement sleep behaviour disorder is characterized by nocturnal violence, increased muscle tone during rapid eye movement sleep and the lack of any other neurological disease. However, idiopathic rapid eye movement sleep behaviour disorder can precede parkinsonism and dementia by several years. Using 3 T magnetic resonance imaging and neuromelanin-sensitive sequences, we previously found that the signal intensity was reduced in the locus coeruleus/subcoeruleus area of patients with Parkinson's disease and rapid eye movement sleep behaviour disorder. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex with neuromelanin-sensitive imaging in 21 patients with idiopathic rapid eye movement sleep behaviour disorder and compared the results with those from 21 age- and gender-matched healthy volunteers. All subjects underwent a clinical examination, motor, cognitive, autonomous, psychological, olfactory and colour vision tests, and rapid eye movement sleep characterization using video-polysomnography and 3 T magnetic resonance imaging. The patients more frequently had preclinical markers of alpha-synucleinopathies, including constipation, olfactory deficits, orthostatic hypotension, and subtle motor impairment. Using neuromelanin-sensitive imaging, reduced signal intensity was identified in the locus coeruleus/subcoeruleus complex of the patients with idiopathic rapid eye movement sleep behaviour. The mean sensitivity of the visual analyses of the signal performed by neuroradiologists who were blind to the clinical diagnoses was 82.5%, and the specificity was 81% for the identification of idiopathic rapid eye movement sleep behaviour. The results confirm that this complex is affected in idiopathic rapid eye movement sleep behaviour (to the same degree as it is affected in Parkinson's disease). Neuromelanin-sensitive imaging provides an early marker of non-dopaminergic alpha-synucleinopathy that can be detected on an individual basis.

Olfactory impairment predicts cognitive decline in early Parkinson's disease

I think this is supportive of those with marked olfactory deficit having a more aggressive disease type... the proportion of PD patients with hyposmia (or worse) is as one would expect... ~90% in those that are recently diagnosed... (~35% were anosmic)

Parkinsonism Relat Disord. 2016 Feb 19. pii: S1353-8020(16)30041-4. doi: 10.1016/j.parkreldis.2016.02.013. [Epub ahead of print]

Fullard ME, Tran B, Xie SX, Toledo JB, Scordia C, Linder C, Purri R, Weintraub D, Duda JE, Chahine LM, Morley JF.

http://www.sciencedirect.com/science/article/pii/S1353802016300414

OBJECTIVE:

To evaluate the association between baseline olfaction and both cross-sectional and longitudinal cognitive assessments, motor symptoms, non-motor symptoms (NMS), and CSF biomarkers in early Parkinson's disease (PD).

METHODS:

Parkinson's Progression Marker's Initiative (PPMI) participants underwent baseline olfactory testing with the University of Pennsylvania Smell Identification Test (UPSIT). Serial assessments included measures of motor symptoms, NMS, neuropsychological assessment, and CSF biomarkers. Up to three years follow-up data were included.

RESULTS:

At baseline, worse olfaction (lowest tertile) was associated with more severe NMS, including anxiety and autonomic symptoms. Those in the lowest olfactory tertile were more likely to report cognitive impairment (37.4%) compared to those in the middle (24.4%) and highest olfactory tertiles (14.2%, p < 0.001). Aβ1-42 was significantly lower, and tau/Aβ1-42 ratio was higher in those with worse olfaction. In longitudinal analyses, lower UPSIT score was associated with greater decline in MoCA score (β = 0.02 [0.01, 0.03], p = 0.001) over time, as were composite measures of UPSIT score and either Aβ1-42 or tau/Aβ1-42 ratio. In a Cox proportional hazards model, a composite measure of olfaction and Aβ1-42 was a significant predictor of conversion from normal cognition to mild cognitive impairment (MCI; i.e., MoCA < 26), with subjects most impaired on both measures being 87% more likely to develop incident MCI (HR = 1.87 [1.16, 3.01], p = 0.01).

CONCLUSIONS:

Worse baseline olfaction is associated with long-term cognitive decline. The addition of AD CSF biomarkers to olfactory testing may increase the likelihood of identifying those at highest risk for cognitive decline and progression to MCI.

Lysosomal Dysfunction and α-Synuclein Aggregation in Parkinson's Disease: Diagnostic Links

Everybody is talking about lysosomal dysfunction these days... thats why I think investigating the link between GBA and PD is so important... may have very real relevance to sporadic PD...

Mov Disord. 2016 Feb 29. doi: 10.1002/mds.26562. [Epub ahead of print]

Moors T, Paciotti S, Chiasserini D, Calabresi P, Parnetti L, Beccari T, van de Berg WD.

Lysosomal impairment is increasingly recognized as a central event in the pathophysiology of PD. Genetic associations between lysosomal storage disorders, including Gaucher disease and PD, highlight common risk factors and pathological mechanisms. Because the autophagy-lysosomal system is involved in the intralysosomal hydrolysis of dysfunctional proteins, lysosomal impairment may contribute to α-synuclein aggregation in PD. The degradation of α-synuclein is a complex process involving different proteolytic mechanisms depending on protein burden, folding, posttranslational modifications, and yet unknown factors. In this review, evidence for lysosomal dysfunction in PD and its intimate relationship with α-synuclein aggregation are discussed, after which the question of whether lysosomal proteins may serve as diagnostic biomarkers for PD is addressed. Changes in lysosomal enzymes, such as reduced glucocerebrosidase and cathepsin levels, have been observed in affected brain regions in PD patients. The detection of lysosomal proteins in CSF may provide a read-out of lysosomal dysfunction in PD and holds promise for the development of diagnostic PD biomarkers. Initial PD biomarker studies demonstrated altered lysosomal enzyme activities in CSF of PD patients when compared with controls. However, CSF lysosomal enzyme activities alone could not discriminate between PD patients and controls. The combination of CSF lysosomal markers with α-synuclein species and indicators of mitochondrial dysfunction, inflammation, and other pathological proteins in PD may be able to facilitate a more accurate diagnosis of PD. Further CSF biomarker studies are needed to investigate the utility of CSF lysosomal proteins as measures of disease state and disease progression in PD. 

Increased peripheral inflammation in asymptomatic leucine-rich repeat kinase 2 mutation carriers

There have been reports of changes in peripheral inflammatory markers in patients with PD, but I don't recall reports in non-manifesting carriers of strong genetic risk factors for PD...

Mov Disord. 2016 Feb 25. doi: 10.1002/mds.26529. [Epub ahead of print]

Dzamko N, Rowe DB, Halliday GM.

BACKGROUND:

We aimed to determine if peripheral or central inflammatory cytokines are altered in healthy subjects carrying a leucine-rich repeat kinase 2 (LRRK2) G2019S mutation, and thus genetically at risk of Parkinson's disease (PD). We also aimed to identify differences in inflammatory cytokines between LRRK2 G2019S-associated and idiopathic PD once the disease manifests.

METHODS:

Participants were genetically screened and phenotyped, and biological samples were collected and stored by the Michael J. Fox Foundation LRRK2 Cohort Consortium. Serum samples and matching clinical data were obtained from 71 asymptomatic LRRK2 G2019S mutation carriers (CSF n = 25), 75 neurologically normal controls (CSF n = 22), 75 idiopathic PD patients (CSF n = 29), and 76 PD patients with a LRRK2 G2019S mutation (CSF n = 20). Inflammatory cytokines were measured using multiplex enzyme-linked immunosorbent assays.

RESULTS:

Serum levels of interleukin 1 beta could discriminate asymptomatic LRRK2 G2019S mutation carriers from controls, with a high inflammatory subgroup of carriers identified. This subgroup was significantly higher in a number of PD-implicated pro-inflammatory cytokines. Once PD had manifest, LRRK2 G2019S patients were discriminated from idiopathic PD by higher serum platelet-derived growth factor, and higher CSF vascular endothelial growth factor and interleukin 8.

CONCLUSIONS:

The results suggest that peripheral inflammation is higher in a percentage of subjects carrying the LRRK2 G2019S mutation. Replication and longitudinal follow-up is required to determine whether the increased peripheral cytokines can predict clinical PD. Importantly, these biological changes were observed prior to the clinical manifestations thought to herald PD.

ɑ-Synuclein strains and the variable pathologies of synucleinopathies

More on the prion hypothesis of Parkinson's disease and related conditions...

J Neurochem. 2016 Feb 29. doi: 10.1111/jnc.13595. [Epub ahead of print]

Peelaerts W, Baekelandt V.

http://onlinelibrary.wiley.com/doi/10.1111/jnc.13595/abstract;jsessionid=19B4DD4A84BB14BCAB704D2D7D9CAB0D.f03t03

Several decades ago, a mysterious transmissible agent was found responsible for a group of progressive and lethal encephalopathies affecting the nervous system of both animals and humans. This infectious agent showed a strain-encoded manner of inheritance even though it lacked nucleic acids. The identification of infectious proteins resolved this apparent conundrum. Misfolded infectious protein particles, or prions, were found to exist as conformational isomers with a unique fingerprint that can be faithfully passaged to next generations. Protein-based strain-encoded inheritance is characterized by strain-specific infectivity and symptomatology. It is found in diverse organisms, such as yeast, fungi and mammals. Now, this concept is revisited to examine the pathological role of amyloid proteins involved in neurodegenerative diseases where it might underlie certain types of dementia and motor-related neurodegenerative disorders. Given the discovery of the SNCA gene and the identification of its gene product, ɑ-synuclein (ɑ-SYN), as the main histopathological component of Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA), the scientific community was left puzzled by the fact that a single protein appeared to be involved in different diseases with diverging clinical phenotypes. Recent studies are now indicating that ɑ-SYN may act in a way similar to prions and that ɑ-SYN misfolded structural variants may behave as strains with distinct biochemical and functional properties inducing specific phenotypic traits, which might finally provide an explanation for the clinical heterogeneity observed between PD, MSA and DLB patients. These crucial new findings may pave the way for unexplored therapeutic avenues and identification of new potential biomarkers.

Association Between Parkinson's Disease and Inflammatory Bowel Disease: a Nationwide Taiwanese Retrospective Cohort Study

There is some plausibility here... but not all studies point the same way. May be some biological similarities, genetic homogeneity, or inflammation in the gut per se as a risk factor. The strengthening of association with hypertension and CAD here is a bit strange. We previously published on Crohn's and PD genetic comorbidity (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888265/)

Inflamm Bowel Dis. 2016 Feb 24. [Epub ahead of print]

Lin JC, Lin CS, Hsu CW, Lin CL, Kao CH.

http://journals.lww.com/ibdjournal/pages/articleviewer.aspx?year=9000&issue=00000&article=98896&type=abstract

OBJECTIVES:

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder. Previous studies have suggested that chronic systemic inflammation increases the risk of Parkinson's disease (PD). This study examined the effects of IBD on the development of PD.

METHODS:

In a nationwide population-based cohort of 23.22 million insured residents of Taiwan aged ≥ 20 years, we compared people diagnosed with IBD during 2000 to 2011 (n = 8373) with IBD-free individuals. Patients with PD were identified in the National Health Insurance Research Database. Using univariable and multivariable Cox proportion hazard regression models, we estimated the adjusted hazard ratio (aHR) for PD with a 95% confidence interval (CI) with adjustment for age, sex, and comorbidities.

RESULTS:

In the cohort, IBD was associated with an increased incidence of PD (crude hazard ratio = 1.43, 95% CI = 1.15-1.79). The risk was highest among individuals with Crohn's disease (aHR = 1.40, 95% CI = 1.11-1.77). In the multivariable model, the risk of PD was increased for men (aHR = 1.28, 95% CI = 1.05-1.56) and higher for patients with hypertension (aHR = 1.72, 95% CI = 1.33-2.24), coronary artery disease (aHR = 1.31, 95% CI = 1.04-1.66), or depression (aHR = 2.51, 95% CI = 1.82-3.46).

CONCLUSIONS:

We suggest that IBD is associated with an increased risk of PD. Patients with IBD should be aware of the potential risk for PD development.

Electroencephalographic prodromal markers of dementia across conscious states in Parkinson's disease.

This study explores an exciting new potential PD biomarker: EEG recordings during sleep - something I certainly hadn't heard much about up until now.

 The same neural system implicated in PD dementia (the cholinergic system) is also known to be involved in regulating sleep. 

The EEG measures used in this study appear potentially useful as a marker for the development of dementia among patients with PD, but further studies will be needed for validation.

We know that sleep disorders (such as RBD) are associated with, and occasionally precede, Parkinson's, so perhaps sleep EEG might even be useful as a pre-motor biomarker as well.

J Rehabil Med. 2016 Feb 4. doi: 10.2340/16501977-2051. [Epub ahead of print]
Hokstad A, Indredavik B, Bernhardt J, Langhammer B, Gunnes M, Lundemo C, Bovim MR, Askim T.

Abstract:
In Parkinson's disease, electroencephalographic abnormalities during wakefulness and non-rapid eye movement sleep (spindles) were found to be predictive biomarkers of dementia. Because rapid eye movement sleep is regulated by the cholinergic system, which shows early degeneration in Parkinson's disease with cognitive impairment, anomalies during this sleep stage might mirror dementia development. In this prospective study, we examined baseline electroencephalographic absolute spectral power across three states of consciousness (non-rapid eye movement sleep, rapid eye movement sleep, and wakefulness) in 68 non-demented patients with Parkinson's disease and 44 healthy controls. All participants underwent baseline polysomnographic recordings and a comprehensive neuropsychological assessment. Power spectral analyses were performed on standard frequency bands. Dominant occipital frequency during wakefulness and ratios of slow-to-fast frequencies during rapid eye movement sleep and wakefulness were also computed. At follow-up (an average 4.5 years after baseline), 18 patients with Parkinson's disease had developed dementia and 50 patients remained dementia-free. In rapid eye movement sleep, patients with Parkinson's disease who later developed dementia showed, at baseline, higher absolute power in delta and theta bands and a higher slowing ratio, especially in temporal, parietal, and occipital regions, compared to patients who remained dementia-free and controls. In non-rapid eye movement sleep, lower baseline sigma power in parietal cortical regions also predicted development of dementia. During wakefulness, patients with Parkinson's disease who later developed dementia showed lower dominant occipital frequency as well as higher delta and slowing ratio compared to patients who remained dementia-free and controls. At baseline, higher slowing ratios in temporo-occipital regions during rapid eye movement sleep were associated with poor performance on visuospatial tests in patients with Parkinson's disease. Using receiver operating characteristic curves, we found that best predictors of dementia in Parkinson's disease were rapid eye movement sleep slowing ratios in posterior regions, wakefulness slowing ratios in temporal areas, and lower dominant occipital frequency. These results suggest that electroencephalographic slowing during sleep is a new promising predictive biomarker for Parkinson's disease dementia, perhaps as a marker of cholinergic denervation.

What a gastrointestinal biopsy can tell us about Parkinson's disease?

There's definitely mileage in continuing to explore gut for biomarkers... defining the appearances in healthy people is key since positive staining for alpha-synuclein is common in controls... but the conformation of this may dictate what is and what is not pathological...

Neurogastroenterol Motil. 2016 Feb 23. doi: 10.1111/nmo.12797. [Epub ahead of print]

Corbillé AG, Clairembault T, Coron E, Leclair-Visonneau L, Preterre C, Neunlist M, Derkinderen P.

BACKGROUND:

The intraneuronal inclusions called Lewy bodies and neurites, which represent the characteristic pathological changes in Parkinson's disease, are found in the enteric neurons in the great majority of parkinsonian patients. This observation led to a substantial amount of research over the last few years in order to develop a minimally invasive diagnostic procedure in living patients based on gastrointestinal (GI) biopsies.

PURPOSE:

In this review, we will begin by discussing the studies that focused on the detection of Lewy bodies and neurites in GI biopsies, then broaden the discussion to the pathological changes that also occur in the enteric glial cells and intestinal epithelial cells. We conclude by proposing that a GI biopsy could represent a unique window to assess the whole pathological process of the brain in Parkinson's disease.

© 2016 John Wiley & Sons Ltd.