1.

Neurology

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 2018 Sep 19. Smartphone motor testingto distinguish idiopathic REM sleep behavior disorder, controls, and PD.

Abstract

OBJECTIVE:

We sought to identify motor features that would allow thedelineation of individuals with sleep study-confirmed idiopathic REM sleepbehavior disorder (iRBD) from controls and Parkinson disease (PD)using a customized smartphone application.

METHODS:

A total of 334 PD, 104 iRBD, and 84 control participants performed7 tasks to evaluate voice, balance, gait, finger tapping, reaction time, resttremor, and postural tremor. Smartphone recordings were collected both inclinic and at home under noncontrolled conditions over several days. Allparticipants underwent detailed parallel in-clinic assessments. Using only thesmartphone sensor recordings, we sought to (1) discriminate whether theparticipant had iRBD or PD and (2) identify which of the above 7 motor taskswere most salient in distinguishing groups.

RESULTS:

Statistically significant differences based on these 7 tasks wereobserved between the 3 groups. For the 3 pairwise discriminatory comparisons,(1) controls vs iRBD, (2) controls vs PD, and (3) iRBD vs PD, the meansensitivity and specificity values ranged from 84.6% to 91.9%. Postural tremor,rest tremor, and voice were the most discriminatory tasks overall, whereas thereaction time was least discriminatory.

CONCLUSIONS:

Prodromal forms of PD include the sleep disorder iRBD, wheresubtle motor impairment can be detected using clinician-based rating scales(e.g., Unified Parkinson"s Disease RatingScale), which may lack the sensitivity to detect and track granular change.Consumer grade smartphones can be used to accurately separate not only iRBDfrom controls but also iRBD from PD participants, providing a growing consensusfor the utility of digital biomarkers in early and prodromal PD.

 

 

2. J Clin Invest. 2018 Sep 18. Regularizingfiring patterns of rat subthalamic neurons ameliorates parkinsonian motordeficits.

Abstract

The subthalamic nucleus (STN) is aneffective therapeutic target for deep brain stimulation (DBS) for Parkinson"sdisease (PD) and histamine level is elevated in the basal ganglia in PDpatients. However, the endogenous histaminergic modulation on STN neuronalactivities and the neuronal mechanism underlying STN-DBS are unknown. Here wereport that STN neuronal firing patterns are more crucial than firing rates formotor control. Histamine excited STN neurons, but paradoxically amelioratedparkinsonian motor deficits, which we attributed to regularizing firingpatterns of STN neurons via HCN2 channel coupled to H2 receptor. Intriguingly,DBS increased histamine release in the STN and regularized STN neuronal firingpatterns under parkinsonian conditions. HCN2 contributed to the DBS-inducedregularization of neuronal firing patterns, suppression of excessive beta oscillations,and alleviation of motor deficits in PD. The results reveal an indispensablerole for regularizing STN neuronal firing patterns in amelioration ofparkinsonian motor dysfunction and a functional compensation for histamine inparkinsonian basal ganglia circuitry. The findings provide insights intomechanisms of STN-DBS as well as potential therapeutic targets and STN-DBSstrategies for PD.

 

 

3. Ann Neurol. 2018 Sep 17.

β

2-adrenoreceptormedications and risk of Parkinson disease.

Abstract

OBJECTIVE:

A recent study observed a two-fold greaterrisk of Parkinson disease (PD) in relation to the β2-adrenoreceptor antagonistpropranolol and a markedly lower risk of PD for the β2-adrenoreceptor agonistsalbutamol. We examined whether confounding by clinical indication for thesemedications, i.e. tremor and smoking-related pulmonary conditions, explainedthese associations.

 

METHODS:

In a large, population-based case-controlstudy of United States Medicare beneficiaries in 2009 with diagnosis codes,procedure codes, and prescription data (48,295 incident PD cases, 52,324controls), we examined the risk of PD in relation to use of selected βantagonists (propranolol, carvedilol, metoprolol), the β2 agonist salbutamol,and other medications used for the same clinical indications (primidone, inhaledcorticosteroids). We adjusted for demographics, smoking, and overall use ofmedical care. We then examined the effect of also adjusting for clinicalindication and applying medication exposure lagging.

 

RESULTS:

Propranolol appeared to increase PD risk(odds ratio [OR]=3.62, 95% confidence interval [CI] 3.31-3.96). When weadjusted for tremor or abnormal involuntary movement prior to the PDdiagnosis/reference date and lagged propranolol exposure, the association was0.97 (95% CI 0.80-1.18). Primidone, also used for tremor, was similarlysensitive to this adjustment and lagging. β antagonists not indicated fortremor appeared to reduce PD risk (carvedilol OR=0.77, 95% CI 0.73-0.81;metoprolol OR=0.94, 95% CI 0.91-0.97) and were insensitive to adjustment forindications and lagging. Neither salbutamol nor inhaled corticosteroids wereconsistently associated with PD risk.

 

INTERPRETATION:

β

2-adrenoreceptor agonists and antagonists

do not appear to alter PD risk.

Thisarticle is protected by copyright. All rights reserved.

 

 

4. Prog Neurobiol. 2018 Sep 13. Newinsights into the complex role of mitochondria in Parkinson"s disease.

Abstract

New discoveries providing insights intomitochondrial bioenergetics, their dynamic interactions as well as their rolein cellular homeostasis have dramatically advanced our understanding of theneurodegenerative process of Parkinson"s disease (PD). Respiratory chainimpairment is a key feature in sporadic PD patients and there is growingevidence that links proteins encoded by PD-associated genes to disturbances inmitochondrial function. Against the backdrop of latest advances in thedevelopment of PD treatments that target mitochondria, we aim to give an overviewof the literature published in the last three decades on the significance ofmitochondria in the pathogenesis of PD. We describe the contribution ofmitochondrial genome alterations and PD-associated genes to mitochondrialmaintenance. We highlight mitophagy as a key mechanism in neurodegeneration.Moreover, we focus on the reciprocal interaction between alpha-synucleinaggregation and mitochondrial dysfunction. We discuss a novel traffickingpathway involving mitochondrial-derived vesicles within the context of PD andprovide a synopsis of the most recently emerging topics in PD research withrespect to mitochondria. This includes the relationship between mitochondriaand cell-mediated immunity, the ER-mitochondria axis, sirtuin-mediated mitochondrialstress response and the role of micro RNAs in the aetiology of PD. In addition,recent studies have challenged the neuro-centric view of PD pathology, movingmicroglia and astrocytes into the research spotlight. Greater insights intothese mechanisms may hold the key for the development of novel targetedtherapies, addressing the need for a disease-modifying treatment, which hasremained elusive to date.

 

 

5. Brain. 2018 Sep 12. doi:10.1093/brain/awy240. Apathy in rapid eye movement sleep behaviour disorder isassociated with serotonin depletion in the dorsal raphe nucleus.

Abstract

Apathy is a common and under-recognizeddisorder that often emerges in the prodromal phase of Parkinsonian diseases.The mechanism by which this occurs is not known, but recent evidence frompatients with established Parkinson"s disease suggests that serotonergicdysfunction may play a role. The integrity of the raphe serotonergic system canbe assessed alongside dopaminergic basal ganglia imaging using the radioligand123I-ioflupane, which binds both serotonin and dopamine transporters. Toinvestigate the relative roles of these neurotransmitters in prodromalparkinsonism, we imaged patients with idiopathic rapid eye movement sleepbehaviour disorder, the majority of whom will develop a parkinsonian disorderin future. Forty-three patients underwent brain imaging with 123I-ioflupanesingle photon emission computed tomography and structural MRI. Apathy wasquantified using the Lille Apathy Rating Scale. Other clinical parkinsonianfeatures were assessed using standard measures.

A negative correlation was observed between apathy severity andserotonergic 123I-ioflupane signal in the dorsal raphe nucleus (r = -0.55, P< 0.001). There was no significant correlation between apathy severity andbasal ganglia dopaminergic signal, nor between dorsal raphe signal and otherneuropsychiatric scores

. This specific association between apathy and raphe123I-ioflupane signal suggests that the serotonergic system might represent atarget for the treatment of apathy.

 

 

6. Proc Natl Acad Sci U S A. 2018 Sep 12. LRRK2and its substrate Rab GTPases are sequentially targeted onto stressed lysosomesand maintain their homeostasis.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) hasbeen associated with a variety of human diseases, including Parkinson"s diseaseand Crohn"s disease, whereas LRRK2 deficiency leads to accumulation of abnormallysosomes in aged animals. However, the cellular roles and mechanisms ofLRRK2-mediated lysosomal regulation have remained elusive. Here, we reveal amechanism of stress-induced lysosomal response by LRRK2 and its target Rab GTPases.Lysosomal overload stress induced the recruitment of endogenous LRRK2 ontolysosomal membranes and activated LRRK2. An upstream adaptor Rab7L1 (Rab29)promoted the lysosomal recruitment of LRRK2. Subsequent family-wide screeningof Rab GTPases that may act downstream of LRRK2 translocation revealed that

Rab8a and Rab10

were specificallyaccumulated on overloaded lysosomes dependent on their phosphorylation byLRRK2. Rab7L1-mediated lysosomal targeting of LRRK2 attenuated thestress-induced lysosomal enlargement and promoted lysosomal secretion, whereasRab8 stabilized by LRRK2 on stressed lysosomes suppressed lysosomal enlargementand Rab10 promoted lysosomal secretion, respectively. These effects weremediated by the recruitment of Rab8/10 effectors EHBP1 and EHBP1L1. LRRK2deficiency augmented the chloroquine-induced lysosomal vacuolation of renaltubules in vivo.

These results implicatethe stress-responsive machinery composed of Rab7L1, LRRK2, phosphorylatedRab8/10, and their downstream effectors in the maintenance of lysosomalhomeostasis.

 

 

7. Proc Natl Acad Sci U S A. 2018 Sep18;115(38):E8844-E8853. doi: 10.1073/pnas.1721136115. Epub 2018 Sep 5.

Altered ER-mitochondria contact impactsmitochondria calcium homeostasis and contributes to neurodegeneration in vivoin disease models.

Abstract

Calcium (Ca2+) homeostasis is essentialfor neuronal function and survival. Altered Ca2+ homeostasis has beenconsistently observed in neurological diseases. How Ca2+ homeostasis isachieved in various cellular compartments of disease-relevant cell types is notwell understood. Here we show in Drosophila Parkinson"s disease (PD) modelsthat Ca2+ transport from the endoplasmic reticulum (ER) to mitochondria throughthe ER-mitochondria contact site (ERMCS) critically regulates mitochondrialCa2+ (mito-Ca2+) homeostasis in dopaminergic (DA) neurons, and that thePD-associated PINK1 protein modulates this process. In PINK1 mutant DA neurons,the ERMCS is strengthened and mito-Ca2+ level is elevated, resulting inmitochondrial enlargement and neuronal death.

Miro, a well-characterized component of the mitochondrial traffickingmachinery, mediates the effects of PINK1 on mito-Ca2+ and mitochondrialmorphology, apparently in a transport-independent manner.

Mirooverexpression mimics PINK1 loss-of-function effect, whereas inhibition of Miroor components of the ERMCS, or pharmacological modulation of ERMCS function,rescued PINK1 mutant phenotypes. Mito-Ca2+ homeostasis is also altered in theLRRK2-G2019S model of PD and the PAR-1/MARK model of neurodegeneration, andgenetic or pharmacological restoration of mito-Ca2+ level is beneficial inthese models. Our results highlight the importance of

mito-Ca2+ homeostasis maintained by Miro and the ERMCS to mitochondrialphysiology and neuronal integrity.

Targeting this mito-Ca2+ homeostasispathway holds promise for a therapeutic strategy for neurodegenerativediseases.

 

 

8. Prog Neurobiol. 2018 Oct;169:158-171.doi: 10.1016/j.pneurobio.2018.06.010. Epub 2018 Jul 3.

Non-cell-autonomous actions ofα-synuclein: Implications in glial synucleinopathies.

Abstract

Many neurodegenerative diseases arederived from the combined consequences of genetic and environmental factors.One of the common features implicated in the neurodegenerative processes isaggregation of disease-specific neuronal proteins. These proteins areaccumulated not only directly in neurons, but also indirectly involve glialcells. Whereas the focus of research has been directed towards the impacts ofprotein aggregation upon neurons, the influence that it exerts on glial cellshas been relatively overlooked. Recent studies, however, provide strongevidence on pathogenic responses of glial cells originated from theneuron-derived protein aggregates. Here, we critically examine the latestadvancement in investigating how glial cells are activated in neurodegenerativedisorders that are associated with α-synuclein aggregates. Often referred to assynucleinopathies, these include Parkinson disease, dementia with Lewy bodies,and multiple system atrophy. To further illustrate, we would discuss paracrineactions of α-synuclein aggregates secreted from neuronal cells in promotingpathogenic reactions from various types of glia and evaluate thenon-cell-autonomous mechanism compared to a cell-autonomous one. Such analysesof the impacts of glial responses in neurodegenerative diseases, in the longterm, could be further utilized in developing different treatments of thediseases and potentially discovering new drugs.

 

 

9. Brain. 2018 Aug 24. doi:10.1093/brain/awy217. [Epub ahead of print]

Parkinsonian signs in patients withcervical dystonia treated with pallidal deep brain stimulation.

Abstract

Pallidal deep brain stimulation is anestablished treatment in patients with dystonia. However, evidence from caseseries or uncontrolled studies suggests that it may lead in some patients tospecific parkinsonian symptoms such as freezing of gait, micrographia, andbradykinesia. We investigated parkinsonian signs using the Movement Disorder SocietyUnified Parkinson"s Disease Rating Scale motor score by means ofobserver-blinded video ratings in a group of 29 patients treated with pallidalstimulation and a non-surgical control group of 22 patients, both withpredominant cervical dystonia. Additional assessments included MRI-based modelsof volume of neural tissue activated to investigate areas of stimulationrelated to dystonic symptom control and those likely to induce parkinsoniansigns as well as an EMG analysis to investigate functional vicinity ofstimulation fields to the pyramidal tract. Compared with controls, stimulatedpatients had significantly higher motor scores (median, 25th-75th percentile:14.0, 8.0-19.5 versus 3.0, 2.0-8.0; P < 0.0001), as well as bradykinesia(8.0, 6.0-14.0 versus 2.0, 0.0-3.0; P < 0.0001) and axial motor subscores(2.0, 1.0-4.0 versus 0.0, 0.0-1.0; P = 0.0002), while rigidity and tremorsubscores were not different between groups. Parkinsonian signs were partiallyreversible upon switching stimulation off for a median of 90 min in a subset of19 patients tolerating this condition.

Furthermore,the stimulation group reported more features of freezing of gait on aquestionnaire basis. Quality of life was better in stimulated patients comparedwith control patients, but parkinsonian signs were negatively associated withquality of life.

In the descriptive imaging analysis maximum efficacy fordystonia improvement projected to the posteroventrolateral internal pallidumwith overlapping clusters driving severity of bradykinesia and axial motorsymptoms. The severities of parkinsonian signs were not correlated withfunctional vicinity to the pyramidal tract as assessed by EMG. In conclusion,

parkinsonian signs, particularlybradykinesia and axial motor signs, due to pallidal stimulation in dystonicpatients are frequent and negatively impact on motor functioning and quality oflife.

Therefore, patients with

pallidalstimulation should be monitored closely for such signs both in clinical routineand future clinical trials.

Spread of current outside the internal pallidumis an unlikely explanation for this phenomenon, which seems to be caused bystimulation of neural elements within the stimulation target volume.

 

 

10. Brain. 2018 Aug 24. doi:10.1093/brain/awy216. [Epub ahead of print]

Balance control systems in Parkinson"sdisease and the impact of pedunculopontine area stimulation.

Abstract

Impaired balance is a major contributor tofalls and diminished quality of life in Parkinson"s disease, yet thepathophysiology is poorly understood. Here, we assessed if patients withParkinson"s disease and severe clinical balance impairment have deficits in theintermittent and continuous control systems proposed to maintain uprightstance, and furthermore, whether such deficits are potentially reversible, withthe experimental therapy of pedunculopontine nucleus deep brain stimulation.Two subject groups were assessed: (i) 13 patients with Parkinson"s disease andsevere clinical balance impairment, implanted with pedunculopontine nucleusdeep brain stimulators; and (ii) 13 healthy control subjects. Patients wereassessed in the OFF medication state and blinded to two conditions; off and onpedunculopontine nucleus stimulation. Postural sway data (deviations in centreof pressure) were collected during quiet stance using posturography.Intermittent control of sway was assessed by calculating the frequency ofintermittent switching behaviour (discontinuities), derived using awavelet-based transformation of the sway time series.

Continuous control of sway was assessed with aproportional-integral-derivative (PID) controller model using ballisticreaction time as a measure of feedback delay.

Clinical balance impairmentwas assessed using the "pull test" to rate postural reflexes and by ratingattempts to arise from sitting to standing. Patients with Parkinson"s diseasedemonstrated reduced intermittent switching of postural sway compared withhealthy controls. Patients also had abnormal feedback gains in postural swayaccording to the PID model.

Pedunculopontinenucleus stimulation improved intermittent switching of postural sway, feedbackgains in the PID model and clinical balance impairment.

Clinical balanceimpairment correlated with

intermittentswitching of postural sway (rho = - 0.705, P < 0.001) and feedback gains inthe PID model (rho = 0.619, P = 0.011).

These results suggest thatdysfunctional intermittent and continuous control systems may contribute to thepathophysiology of clinical balance impairment in Parkinson"s disease.

Clinical balance impairment and theirrelated control system deficits are potentially reversible, as demonstrated bytheir improvement with pedunculopontine nucleus deep brain stimulation.

 

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