"Gunslinger's gait": a new cause of unilaterally reduced arm swing.

This made me laugh earlier in the week... great article about the walking pattern of high-ranking Russian officials!

BMJ. 2015 Dec 14;351:h6141. doi: 10.1136/bmj.h6141.

Araújo R, Ferreira JJ, Antonini A, Bloem BR.

OBJECTIVE:

 To postulate a new possible cause of a unilaterally reduced arm swing in addition to the known medical conditions such as shoulder pathology, Erb's palsy, stroke, and Parkinson's disease.

METHODS:

 Analysis of YouTube videos depicting the gait of highly ranked Russian officials.

RESULTS:

 We found a similar walking pattern in President Vladimir Putin, Prime Minister Dmitry Medvedev and three other highly ranked Russian officials, all presenting with a consistently reduced right arm swing in the absence of other overt neurological abnormalities.

CONCLUSIONS:

 We propose that this new gait pattern, which we term "gunslinger's gait," may result from a behavioural adaptation, possibly triggered by KGB or other forms of weapons training where trainees are taught to keep their right hand close to the chest while walking, allowing them to quickly draw a gun when faced with a foe. This should be included in the differential diagnosis of a unilaterally reduced arm swing.

Whole-Exome Sequencing in Familial Parkinson Disease.

Here we see whole exome sequencing used to potentially uncover more of the missing heritability of PD...these now need to be confirmed in other data sets...

JAMA Neurol. 2015 Nov 23:1-8. doi: 10.1001/jamaneurol.2015.3266. [Epub ahead of print]

Farlow JL, Robak LA, Hetrick K, Bowling K, Boerwinkle E, Coban-Akdemir ZH, Gambin T, Gibbs RA, Gu S, Jain P, Jankovic J, Jhangiani S, Kaw K, Lai D, Lin H, Ling H, Liu Y, Lupski JR, Muzny D, Porter P, Pugh E, White J, Doheny K, Myers RM, Shulman JM, Foroud T.

http://archneur.jamanetwork.com/article.aspx?articleid=2470417

IMPORTANCE:

Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.

OBJECTIVE:

To identify genetic variants contributing to disease risk in familial PD.

DESIGN, SETTING, AND PARTICIPANTS:

A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.

MAIN OUTCOMES AND MEASURES:

Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.

RESULTS:

The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.

CONCLUSIONS AND RELEVANCE:

TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

Familial Aggregation and Co-Aggregation of Essential Tremor and Parkinson's Disease.

Certainly we see this in the clinic sometimes...

Neuroepidemiology. 2015 Nov 26;46(1):31-36. [Epub ahead of print]

Louis ED, Clark L, Ottman R.

http://www.karger.com/Article/Abstract/442021

BACKGROUND:

Current data suggest that the 2 common tremor disorders, essential tremor (ET) and Parkinson's disease (PD), may be associated with one another. Familial aggregation studies allow one to further explore their relatedness.

METHODS:

Probands with ET (n = 110), PD (n = 130) or both ET and PD (n = 27) and control probands (n = 177) reported whether they had relatives with these diseases or with non-specific tremor.

RESULTS:

A greater proportion of ET probands than control probands reported relatives with ET (30.0 vs. 2.8%, p < 0.001), non-specific tremor (38.2 vs. 13.6%, p < 0.001) and both ET and PD in different relatives (6.4 vs. 0.6%, p = 0.004). A greater proportion of PD probands than control probands reported relatives with PD (20.0 vs. 8.5%, p = 0.003), ET (11.5 vs. 2.8%, p = 0.002) and both ET and PD in different relatives (6.9 vs. 0.6%, p = 0.002).

CONCLUSIONS:

This study provides evidence for the aggregation of ET in ET families and PD in PD families, and the familial co-aggregation of ET and PD.

Oculo-Visual Dysfunction in Parkinson's Disease.

Oculo-visual disturbance is frequently reported in PD. Further characterisation and recognition of when it begins are important, but difficult to study formally. Efforts close to home are underway...!

J Parkinsons Dis. 2015 Nov 24. [Epub ahead of print]

Armstrong RA

http://content.iospress.com/articles/journal-of-parkinsons-disease/jpd150686

This review describes the oculo-visual problems likely to be encountered in Parkinson's disease (PD) with special reference to three questions: (1) are there visual symptoms characteristic of the prodromal phase of PD, (2) is PD dementia associated with specific visual changes, and (3) can visual symptoms help in the differential diagnosis of the parkinsonian syndromes, viz. PD, progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD)? Oculo-visual dysfunction in PD can involve visual acuity, dynamic contrast sensitivity, colour discrimination, pupil reactivity, eye movement, motion perception, and visual processing speeds. In addition, disturbance of visuo-spatial orientation, facial recognition problems, and chronic visual hallucinations may be present. Prodromal features of PD may include autonomic system dysfunction potentially affecting pupil reactivity, abnormal colour vision, abnormal stereopsis associated with postural instability, defects in smooth pursuit eye movements, and deficits in visuo-motor adaptation, especially when accompanied by idiopathic rapid eye movement (REM) sleep behaviour disorder. PD dementia is associated with the exacerbation of many oculo-visual problems but those involving eye movements, visuo-spatial function, and visual hallucinations are most characteristic. Useful diagnostic features in differentiating the parkinsonian symptoms are the presence of visual hallucinations, visuo-spatial problems, and variation in saccadic eye movement dysfunction.

Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression

We are starting to learn much more about the genetic architecture of PD and how genes determine not only ones absolute risk of acquiring PD, but also account for a substantial proportion of the heterogeneity of PD.

Neurobiol Aging. 2015 Sep 30. pii: S0197-4580(15)00471-6. doi: 10.1016/j.neurobiolaging.2015.09.014. [Epub ahead of print]

Davis AA, Andruska KM, Benitez BA, Racette BA, Perlmutter JS, Cruchaga C.

http://www.neurobiologyofaging.org/article/S0197-4580(15)00471-6/abstract

Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression.

Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease.

Very interesting to see the continuation of the work of this group following the first report in 2014...especially given the strong results presented. Phosphorylated alpha-syn in biopsies from all subjects with a syncucleinopathy (PD and PAF) and the importance of the site of sampling reiterated.

Ann Neurol. 2015 Nov 25. doi: 10.1002/ana.24567. [Epub ahead of print]

Donadio V, Incensi A, Piccinini C, Cortelli P, Giannoccaro MP, Baruzzi A, Liguori R.

http://onlinelibrary.wiley.com/doi/10.1002/ana.24567/abstract;jsessionid=7A6E9ECDDD66E229E7E0375AC6674498.f02t01?systemMessage=Wiley+Online+Library+will+have+be+unavailable+on+Saturday+5th+December+from+10%3A00-14%3A00+GMT+%2F+05%3A00-09%3A00+EST+%2F+18%3A00-22%3A00+SGT+for+essential+maintenance.+Apologies+for+the+inconvenience.

OBJECTIVE:

To characterize the expression in skin nerves of native (n-syn) and misfolded phosphorylated (p-syn) α-synucleins in pure autonomic failure (PAF) and idiopathic Parkinson disease (IPD). The specific aims were to: 1) define the importance of n-syn and p-syn as disease biomarkers; 2) ascertain differences in abnormal synuclein skin nerve deposits.

MATERIALS AND METHODS:

We studied 30 patients including 16 well-characterized IPD and 14 patients fulfilling PAF diagnostic criteria and 15 age-matched controls. Subjects underwent skin biopsy from proximal (i.e. cervical) and distal (i.e. thigh and leg) sites to study small nerve fiber and intraneural n-syn and p-syn.

RESULTS:

PAF and IPD showed a length-dependent somatic and autonomic small fiber loss, more severely expressed in patients with higher p-syn load. N-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not evident in any skin sample of controls but was found in all PAF and IPD patients whilst with different skin innervation. In addition, abnormal α-syn deposits were found in all analyzed skin samples in PAF but in only 49% of samples with a higher positivity rate in the proximal site in IPD.

INTERPRETATION:

1) Intraneural p-syn was a reliable in vivo marker of PAF and IPD; 2) neuritic p-syn inclusions differed in PAF and IPD suggesting a different underlying pathogenesis; 3) searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF but it is critical in IPD.

Evaluation of 99mTc-TRODAT-1 SPECT in the diagnosis of Parkinson's disease versus other progressive movement disorders

Consistent with previous studies, there is little to differentiate Parkinson's disease from parkinsonian syndromes here, but as expected essential tremor and vascular PD subjects have better uptake...

Ann Nucl Med. 2015 Nov 26. [Epub ahead of print]

Fallahi B, Esmaeili A, Beiki D, Oveisgharan S, Noorollahi-Moghaddam H, Erfani M, Tafakhori A, Rohani M, Fard-Esfahani A, Emami-Ardekani A, Geramifar P, Eftekhari M.

http://link.springer.com/article/10.1007%2Fs12149-015-1042-y

OBJECTIVE:

Parkinson disease (PD), parkinsonian syndromes (PS) and essential tremor (ET) are different types of movement disorders which share some symptoms resulting in a difficulty of certain diagnosis. This study was conducted to determine the value of 99mTc-TRODAT-1 scan to differentiate PD from ET and other PS cases.

METHODS:

Totally, 75 patients were studied including 29 PD, 6 possible PD, 22 ET and 18 PS cases. A dual-head SPECT-CT was used to perform basal ganglia (BG) imaging following administration of 99mTc-TRODAT-1. The BG uptake values were normalized to whole brain and occipital activity. All patients were followed for 2-22 months to reach a certain diagnosis.

RESULTS:

Patients with ET and drug-induced parkinsonism show significantly higher normalized BG uptake as compared to the other subgroups; however, no significant difference was noted between PD and PS patients. The sensitivity and specificity of the findings for the differentiation between patients with the disease associated versus not associated with BG dysfunction were 80 and 83.3 %, respectively. A predictive positive value of 82.6 % was obtained using an additive scaling index defined as asymmetry and unevenness of uptake in putamen and/or caudate contralateral to the dominant side of current symptoms.

CONCLUSIONS:

99mTc-TRODAT-1 scan is an appropriate method to differentiate PD or PS versus ET. A combination of scan pattern including asymmetry of BG uptake and unevenness of activity in caudate and putamen along with the side of dominant symptoms may be valuable for the differentiation of Parkinson's disease from the other parkinsonian syndromes.

Systematic review and meta-analysis of salivary protein concentration in Parkinson's disease

Our new meta published as a letter in Movement Disorders, therefore no abstract. Of the published studies thus far, it appears that total protein concentration is increased in the saliva of patients with PD. We have to use a method called Standardized Mean Difference (see figure below) because of differences in the way protein concentration was measured. The next question is... what are these proteins?

Mov Disord. 2015 Nov 19. doi: 10.1002/mds.26462. [Epub ahead of print]

Masters JM, Bestwick J, Warner TT, Giovannoni G, Proctor GB, Noyce AJ.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26462/abstract

MDS research criteria for prodromal Parkinson's disease

Hmmm Bayesian methods using likelihood ratios to update age related odds of PD... where have I heard that approach before?? Nonetheless very important to formalise this approach and I think these criteria will be used widely...

Mov Disord. 2015 Oct;30(12):1600-11. doi: 10.1002/mds.26431.

Berg D, Postuma RB, Adler CH, Bloem BR, Chan P, Dubois B, Gasser T, Goetz CG, Halliday G, Joseph L, Lang AE, Liepelt-Scarfone I, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26431/abstract

This article describes research criteria and probability methodology for the diagnosis of prodromal PD. Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Given the lack of clear neuroprotective/disease-modifying therapy for prodromal PD, these criteria were developed for research purposes only. The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty. Certainty estimates rely upon calculation of an individual's risk of having prodromal PD, using a Bayesian naïve classifier. In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios. This diagnostic information combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing. In order to be included, diagnostic markers had to have prospective evidence documenting ability to predict clinical PD. They include motor and nonmotor clinical symptoms, clinical signs, and ancillary diagnostic tests. These criteria represent a first step in the formal delineation of early stages of PD and will require constant updating as more information becomes available. © 2015 International Parkinson and Movement Disorder Society.

REM sleep behavior disorder, as assessed by questionnaire, in G2019S LRRK2 mutation PD and carriers.

Not sure I arrive at the same conclusions here... which should be suffixed with 'in LRRK2 mutation carriers'. There are differences between LRRK2 patients and patients with iPD and these differences likely extend into the pre-diagnostic phase too. That said, I think the RBDSQ is prone to significant inaccuracy... at least that is our experience.

Mov Disord. 2015 Sep 14. doi: 10.1002/mds.26413. [Epub ahead of print]

Saunders-Pullman R, Alcalay RN, Mirelman A, Wang C, Luciano MS, Ortega RA, Glickman A, Raymond D, Mejia-Santana H, Doan N, Johannes B, Yasinovsky K, Ozelius L, Clark L, Orr-Utreger A, Marder K, Giladi N, Bressman SB; AJ LRRK2 Consortium.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26413/abstract;jsessionid=7350378EA434DB1093EE340C20075195.f04t02

BACKGROUND:

Rapid eye movement sleep behavior disorder occurs with idiopathic Parkinson's disease (PD) and often precedes PD. Its frequency in LRRK2-PD and utility as a preclinical marker has not been established.

METHODS:

One hundred forty-four idiopathic PD, 142 LRRK2 G2019S mutation PD, 117 non-manifesting carriers, 93 related noncarriers, and 40 healthy controls completed the Rapid eye movement sleep Behavior Disorder Screening Questionnaire.

RESULTS:

Cut scores were met by 30.6% idiopathic PD, 19.7% LRRK2-PD, 6% nonmanifesting carriers, 20.4% related noncarriers, and 15% controls. The likelihood of abnormal scores was decreased in LRRK2-PD versus idiopathic PD (odds ratio = 0.55, P = 0.03), nonmanifesting carriers versus related noncarriers (OR = 0.25, P < 0.01), and PD of less than 3 years' duration, 1 of 19 LRRK2-PD versus 14 of 41 idiopathic PD (P < 0.05).

CONCLUSIONS:

A lower frequency of abnormal questionnaire scores is seen in LRRK2-PD, especially in early LRRK2-PD, and in nonmanifesting carriers. Therefore, the Rapid eye movement sleep Behavior Disorder Questionnaire is unlikely to serve as a preclinical marker for phenoconversion to PD. © 2015 International Parkinson and Movement Disorder Society.

Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson’s Disease Patients

Once potential biomarkers of a disease are discovered, it is important that they are 'validated' in a group of patients and controls different from the group in which the biomarker was initially discovered.

In this study, the researchers test for the presence of 10 candidate biomarkers (discovered in previous work) in the blood of patients very recently diagnosed with PD and controls.

A particular strength of this study is that the newly diagnosed patients had not yet been prescribed any treatments for Parkinson's. This removes the possibility that PD medications might be having an effect on the biomarker levels and suggests that the biomarkers are reflective of the underlying diseas process.

The researchers makes use of samples from the Parkinson's Progression Markers Initiative (PPMI) demonstrating, how large collaborative projects can help accelerate biomarker discovery.


Santiago JA, & Potashkin JA (2015). Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson's Disease Patients. PloS one, 10 (11) PMID: 26566043

Abstract

Early diagnosis of Parkinson’s disease (PD) continues to be a major challenge in the field. The lack of a robust biomarker to detect early stage PD patients has considerably slowed the progress toward the development of potential therapeutic agents. We have previously evaluated several RNA biomarkers in whole blood from participants enrolled in two independent clinical studies. In these studies, PD patients were medicated, thus, expression of these biomarkers in de novo patients remains unknown. To this end, we tested ten RNA biomarkers in blood samples from 99 untreated PD patients and 101 HC nested in the cross-sectional Parkinson’s Progression Markers Initiative by quantitative real-time PCR. One biomarker out of ten, COPZ1 trended toward significance (nominal p = 0.009) when adjusting for age, sex, and educational level. Further, COPZ1, EFTUD2 and PTBP1 mRNAs correlated with clinical features in PD patients including the Hoehn and Yahr scale, Movement Disorder Society revision of Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA) score. Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN) compared to cognitively impaired PD patients (PD-MCI). Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (≥ 100 mg/dL, pre-diabetes) compared to HC. Collectively, we report the association of three RNA biomarkers, COPZ1, EFTUD2 and PTBP1 with clinical features including cognitive decline in early drug-naïve PD patients. Further, our results show that drug-naïve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD. Evaluation of these potential biomarkers in a larger longitudinal study is warranted.