Saturday, 25 February 2017

Technologies Assessing Limb Bradykinesia in Parkinson's Disease

Very pleased to see this online... the culmination of a lot of hard work from Hasan Hasan who tirelessly re-ran the literature search to keep it up to date. We have tried to be very balanced here and simply present the available tech to assess bradykinesia in PD. We will also aim to keep this up to date by including new technologies every few months to the Google drive version of the table... I hope people will find the resource useful...

J Parkinsons Dis. 2017;7(1):65-77. doi: 10.3233/JPD-160878.
Hasan H, Athauda DS, Foltynie T, Noyce AJ.

BACKGROUND: The MDS-UPDRS (Movement Disorders Society - Unified Parkinson's Disease Rating Scale) is the most widely used scale for rating impairment in PD. Subscores measuring bradykinesia have low reliability that can be subject to rater variability. Novel technological tools can be used to overcome such issues.

OBJECTIVE: To systematically explore and describe the available technologies for measuring limb bradykinesia in PD that were published between 2006 and 2016.

METHODS: A systematic literature search using PubMed (MEDLINE), IEEE Xplore, Web of Science, Scopus and Engineering Village (Compendex and Inspec) databases was performed to identify relevant technologies published until 18 October 2016. RESULTS: 47 technologies assessing bradykinesia in PD were identified, 17 of which offered home and clinic-based assessment whilst 30 provided clinic-based assessment only. Of the eligible studies, 7 were validated in a PD patient population only, whilst 40 were tested in both PD and healthy control groups. 19 of the 47 technologies assessed bradykinesia only, whereas 28 assessed other parkinsonian features as well. 33 technologies have been described in additional PD-related studies, whereas 14 are not known to have been tested beyond the pilot phase.

CONCLUSION: Technology based tools offer advantages including objective motor assessment and home monitoring of symptoms, and can be used to assess response to intervention in clinical trials or routine care. This review provides an up-to-date repository and synthesis of the current literature regarding technology used for assessing limb bradykinesia in PD. The review also discusses the current trends with regards to technology and discusses future directions in development.

Wednesday, 22 February 2017

Identification of candidate cerebrospinal fluid biomarkers in parkinsonism using quantitative proteomics

Good work by Nadia... it was a huge amount of work to gather samples from so many patients... but of course this is really important. You need large numbers to capture the heterogeneity in the diseases. It's been said many times but biomarkers for all of these diseases are desperately needed. This work is definitely a positive step in that direction...

Parkinsonism Relat Disord. 2017 Jan 31. pii: S1353-8020(17)30030-5. doi: 10.1016/j.parkreldis.2017.01.016. [Epub ahead of print]
Magdalinou NK, Noyce AJ, Pinto R, Lindstrom E, Holmén-Larsson J, Holtta M, Blennow K, Morris HR, Skillbäck T, Warner TT, Lees AJ, Pike I, Ward M, Zetterberg H, Gobom J.

INTRODUCTION: Neurodegenerative parkinsonian syndromes have significant clinical and pathological overlap, making early diagnosis difficult. Cerebrospinal fluid (CSF) biomarkers may aid the differentiation of these disorders, but other than α-synuclein and neurofilament light chain protein, which have limited diagnostic power, specific protein biomarkers remain elusive.

OBJECTIVES: To study disease mechanisms and identify possible CSF diagnostic biomarkers through discovery proteomics, which discriminate parkinsonian syndromes from healthy controls.

METHODS: CSF was collected consecutively from 134 participants; Parkinson's disease (n = 26), atypical parkinsonian syndromes (n = 78, including progressive supranuclear palsy (n = 36), multiple system atrophy (n = 28), corticobasal syndrome (n = 14)), and elderly healthy controls (n = 30). Participants were divided into a discovery and a validation set for analysis. The samples were subjected to tryptic digestion, followed by liquid chromatography-mass spectrometry analysis for identification and relative quantification by isobaric labelling. Candidate protein biomarkers were identified based on the relative abundances of the identified tryptic peptides. Their predictive performance was evaluated by analysis of the validation set.

RESULTS: 79 tryptic peptides, derived from 26 proteins were found to differ significantly between atypical parkinsonism patients and controls. They included acute phase/inflammatory markers and neuronal/synaptic markers, which were respectively increased or decreased in atypical parkinsonism, while their levels in PD subjects were intermediate between controls and atypical parkinsonism.

CONCLUSION: Using an unbiased proteomic approach, proteins were identified that were able to differentiate atypical parkinsonian syndrome patients from healthy controls. Our study indicates that markers that may reflect neuronal function and/or plasticity, such as the amyloid precursor protein, and inflammatory markers may hold future promise as candidate biomarkers in parkinsonism.

Wednesday, 15 February 2017

Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players

Great paper by dear friend and colleague Helen Ling... this is one of the strongest indications yet that repetitive head trauma is a risk factor for neuro-degeneration... in this instance it has been suggested in professional footballers who have headed the ball repeatedly... Clearly this does not provide definitive evidence but it is nonetheless a very important paper and one that has great public health importance... However this topic clearly divides people, including doctors... there will be thousands of people that get dementia and parkinsonism that never played football and vice versa thousands of footballers that don't get these diseases during their lives... a selection of media links so that you can see different interpretations...

Acta Neuropathologica
Helen Ling, Huw R. Morris, James W. Neal, Andrew J. Lees, John Hardy, Janice L. Holton, Tamas Revesz, David D. R. Williams

In retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected. Next-of-kin provided consent for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played football for an average of 26 years. Concussion rate was limited in six cases to one episode each during their careers. All cases developed progressive cognitive impairment with an average age at onset of 63.6 years and disease duration of 10 years. Neuropathological examination revealed septal abnormalities in all six post-mortem cases, supportive of a history of chronic repetitive head impacts. Four cases had pathologically confirmed CTE; concomitant pathologies included Alzheimer’s disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. The pathological diagnosis of CTE was established in four individuals according to the latest consensus diagnostic criteria. This finding is probably related to their past prolonged exposure to repetitive head impacts from head-to-player collisions and heading the ball thousands of time throughout their careers. Alzheimer’s disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals. Association football is the most popular sport in the world and the potential link between repetitive head impacts from playing football and CTE as indicated from our findings is of considerable public health interest. Clearly, a definitive link cannot be established in this clinico-pathological series, but our findings support the need for further systematic investigation, including large-scale case–control studies to identify at risk groups of footballers which will justify for the implementation of protective strategies.

Monday, 13 February 2017

Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder

Great work by friends and colleagues on this paper the results within... however the most important question is whether NfL differentiates the really challenging cases from one another. For example, many neurologists would recognise 'text book' PD compared with one of the so-called Parkinson's plus disorder... a smaller number would recognise when there are atypical features in the patient with PD and would therefore try to characterise further or wait until time gave further clues... But there are some patients in which you just do not know. It could be PD or a mimic... it is for those patients that I would love to see a biomarker that really differentiates and I suspect the NfL is not specific enough and more than one marker may be required...

Neurology. 2017 Feb 8. pii: 10.1212/WNL.0000000000003680. doi: 10.1212/WNL.0000000000003680. [Epub ahead of print]
Hansson O, Janelidze S, Hall S, Magdalinou N, Lees AJ, Andreasson U, Norgren N, Linder J, Forsgren L, Constantinescu R, Zetterberg H, Blennow K; Swedish BioFINDER study.

OBJECTIVE: To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders.

METHODS: The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated.

RESULTS: We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73-0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81).

CONCLUSIONS: Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics.

CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that blood NfL levels discriminate between PD and APD.

Evaluating the performance of the Montreal Cognitive Assessment in early stage Parkinson's disease

This may be true but I would argue that the PD patients in PPMI are perhaps not typical of PD patients in general... people participating in such studies tend to be from a higher socioeconomic background and perhaps be better educated. At said, in our PREDICT-PD experience, I do not think that 37% of the controls achieved full marks, which suggests something special about the PPMI patients. Although I would agree with the authors in other respects... I suspect that a number of items in the MoCA may be redundant in the earlier stages of PD...

Parkinsonism Relat Disord. 2017 Jan 28. pii: S1353-8020(17)30029-9. doi: 10.1016/j.parkreldis.2017.01.012. [Epub ahead of print]
Kletzel SL, Hernandez JM, Miskiel EF, Mallinson T, Pape TL.

INTRODUCTION: Mild cognitive impairment is common in Parkinson's disease, even in the early stages, and can be a risk for developing dementia. To properly track development and progression of cognitive impairment, reliable measurement tools are necessary. The Montreal Cognitive Assessment is currently used as a global cognitive screening tool and has been recommended as an abbreviated diagnostic tool to measure mild cognitive impairment in the context of global cognitive function. However psychometric properties of the Montreal Cognitive Assessment in PD have not been assessed in this context.

METHODS: Data were obtained from the Parkinson's Progression Markers Initiative (n = 395). We examine psychometric properties of the Montreal Cognitive Assessment among newly diagnosed Parkinson's disease patients using Rasch analysis.

RESULTS: Only one item misfit the measurement model and principle component analysis indicated the Montreal Cognitive Assessment was unidimensional. Distribution of items calibrations formed a logical hierarchy from least to most challenging. Test items were markedly off-target (i.e., too easy) for this sample; this was also reflected in low person separation reliability. While 37% of participants performed all items correctly indicating a large ceiling effect, 22% of participants obtained a raw score in the range of 21-25 indicating mild cognitive impairment. No meaningful differential item functioning was detected.

CONCLUSION: Results suggest that in the context of early stage Parkinson's disease, the Montreal Cognitive Assessment is a unidimensional measure of global cognitive function. Implications for the use of the Montreal Cognitive Assessment in early stage Parkinson's disease and potential improvements to the assessment are discussed.

Plain English - LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic

This research study compared patients with Parkinson's who carry the commonest gene mutation associated with the disease (called LRRK2),...