Orthostatic tremor: Clinical, electrophysiologic, and treatment findings in 184 patients

This is an unusual tremor disorder... although rare, it is probably more common than we think but diagnosis is frequently delayed for many years. Great to see a large series published... some go on to get Parkinson's over time...

Neurology. 2016 Jan 8. pii: 10.1212/WNL.0000000000002328. [Epub ahead of print]

Hassan A, Ahlskog JE, Matsumoto JY, Milber JM, Bower JH, Wilkinson JR.

OBJECTIVE:

To evaluate the clinical, electrophysiologic, and treatment outcome features of orthostatic tremor (OT) in a large case series.

METHODS:

We performed medical record review of 184 patients who met clinical and electrodiagnostic criteria for OT from 1976 to 2013 at the Mayo Clinic. Demographic, clinical, electrophysiologic, and treatment data were extracted.

RESULTS:

The majority of OT cases were female (63.6%) and mean age at onset was 59.3 years (range 13-85 years). Diagnosis was delayed by a mean of 7.2 years (range 0-44 years). The average tremor frequency was 15.7 Hz (range 12.5-20 Hz), and transmitted to the arms on weight-bearing (95.5%). Patients reported a spectrum of progressive orthostatic leg symptoms, relieved by sitting or leaning. Falls were reported in 24.1%. Coexistent neurologic disorders included essential tremor (22.8%), other tremor (4.9%), and parkinsonism (8.7%). Family history of OT was noted in 4.9%. Of 46 medications trialed, 24 failed to provide any benefit. Benzodiazepines provided at least mild benefit in 55.9%, and moderate to marked benefit in 31.5%; β-blockers (31.0%) and anticonvulsants (25.0%) provided mild benefit, and the remainder were largely ineffective. Medication benefit waned over time. Deep brain stimulation (DBS) was effective in 2 cases.

CONCLUSION:

OT predominantly affects female seniors, and the diagnosis should be considered with any orthostatic-induced leg symptoms, and confirmed by surface EMG. Benzodiazepines are the most efficacious treatment, followed by β-blockers and anticonvulsants. DBS should be further explored for treatment.

Head injury at early ages is associated with risk of Parkinson's disease.

More epidemiological evidence to support the fact that head injury increases risk of PD... is a case-control study so one should be wary of the potential for reverse causality but they excluded injuries in the 10 years prior to diagnosis which may have mitigated some of this...

Parkinsonism Relat Disord. 2015 Dec 19. pii: S1353-8020(15)30056-0. doi: 10.1016/j.parkreldis.2015.12.005. [Epub ahead of print]

Taylor KM, Saint-Hilaire MH, Sudarsky L, Simon DK, Hersh B, Sparrow D, Hu H, Weisskopf MG.

http://www.sciencedirect.com/science/article/pii/S1353802015300560

INTRODUCTION:

The literature on the effect of head injuries on the risk of PD is inconclusive. Some researchers have hypothesized that studies that have seen an effect are simply capturing injury related to pre-clinical PD. However in animal models brain inflammation, which can be initiated by head trauma, has been shown to produce PD-like effects. Furthermore, animal studies have found that early life inflammation in particular is of relevance for PD pathology.

METHODS:

We conducted an unmatched case-control study of 379 neurologist confirmed PD patients and 230 controls from the greater Boston, Massachusetts area with questionnaire data on history of head injury and other covariates. We used multivariable logistic regression to estimate adjusted odds ratios (OR) and their corresponding 95% confidence intervals (CI) for PD.

RESULTS:

When we excluded injuries that occurred less than 10 years prior to the diagnosis of PD (in order to avoid reverse causation), we found an increased risk of PD associated with a head injury that resulted in a loss of consciousness, but it did not reach statistical significance (OR = 1.57; 95% CI = 0.89-2.80). We found a significant (p = 0.04) effect of age at first head injury. For every 5 year earlier age at first head injury with loss of consciousness the OR for PD was 1.37 (95% CI: 1.01-1.86).

CONCLUSION:

Our results suggest that head injury in early life increases the risk of PD.

Copyright © 2015. Published by Elsevier Ltd.

Opicapone as an adjunct to levodopa in patients with Parkinson's disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial

New COMT inhibitor Opicapone... shows its superiority to placebo and non-inferiority compared with entacapone... no definite increase in adverse effects... and once daily dosing certainly attractive for patients and clinicians...

Lancet Neurol. 2015 Dec 22. pii: S1474-4422(15)00336-1. doi: 10.1016/S1474-4422(15)00336-1. [Epub ahead of print]

Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P; Bi-Park 1 investigators.

http://www.sciencedirect.com/science/article/pii/S1474442215003361

BACKGROUND:

Opicapone is a novel, once-daily, potent third-generation catechol-O-methyltransferase inhibitor. We aimed to assess the safety and efficacy of opicapone as an adjunct to levodopa compared with placebo or entacapone in patients with Parkinson's disease and motor fluctuations.

METHODS:

We did a randomised, double-blind, placebo-controlled and active-controlled trial of opicapone as an adjunct to levodopa in patients with Parkinson's disease with end-of-dose motor fluctuations. Patients aged 30-83 years were enrolled at 106 specialist centres across 19 European countries and Russia and were randomly assigned (1:1:1:1:1) by a proprietary computer-generated sequence to oral treatment with opicapone (5 mg, 25 mg, or 50 mg once daily), placebo, or entacapone (200 mg with every levodopa intake) for 14-15 weeks. Patients and investigators (ie, outcome assessors) were masked to treatment allocation. The primary endpoint was the change from baseline to end of study treatment in absolute time in the off state, as assessed by daily paper patient diaries; the primary analysis followed a hierarchical procedure for each opicapone dose in which superiority compared with placebo in the full analysis set was first tested and then, if positive, non-inferiority to entacapone was tested in the per-protocol set with a margin of 30 min. This trial is registered with EudraCT, 2010-021860-13, and ClinicalTrials.gov, NCT01568073.

FINDINGS:

Between March 31, 2011, and Nov 30, 2013, of 679 patients screened, 600 were randomly assigned. 590 patients were included in the full analysis set (120 in the placebo group, 120 in the entacapone group, 119 in the opicapone 5 mg group, 116 in the opicapone 25 mg group, and 115 in the opicapone 50 mg group) and 537 in the per-protocol set (112 in the placebo group, 104 in the entacapone group, 110 in the opicapone 5 mg group, 105 in the opicapone 25 mg group, and 106 in the opicapone 50 mg group). The mean change in time in the off state was -56·0 min (SE 13·4; 95% CI -82·3 to -29·7) for placebo, -96·3 min (13·4; -122·6 to -70·0) for entacapone, -91·3 min (13·5; -117·7 to -64·8) for opicapone 5 mg, -85·9 min (13·7; -112·8 to -59·1) for opicapone 25 mg, and -116·8 min (14·0; -144·2 to -89·4) for opicapone 50 mg. Treatment with opicapone 50 mg was superior to placebo (mean difference in change from baseline -60·8 min, 95% CI -97·2 to -24·4; p=0·0015) and non-inferior to entacapone (-26·2 min, -63·8 to 11·4; p=0·0051). Treatment with opicapone 5 mg (p=0·056) or 25 mg (p=0·080) was not significantly different from treatment with placebo. Treatment-emergent adverse events were reported in 60 (50%) of 121 patients in the placebo group, 69 (57%) of 122 in the entacapone group, 63 (52%) of 122 in the opicapone 5 mg group, 65 (55%) of 119 in the opicapone 25 mg group, and 62 (54%) of 115 in the opicapone 50 mg group. The most common adverse events were dyskinesia (in five patients in the placebo group, ten in the entacapone group, 17 in the opicapone 5 mg group, nine in the opicapone 25 mg group, and 18 in the opicapone 50 mg group), insomnia (in one, seven, two, seven, and seven patients, respectively), and constipation (in three, five, four, none, and seven patients, respectively). Serious adverse events were reported in six patients in the placebo group, eight in the entacapone group, four each in the opicapone 5 mg and opicapone 50 mg groups, and one in the opicapone 25 mg group.

INTERPRETATION:

The addition of opicapone 50 mg to levodopa treatment in patients with Parkinson's disease and end-of-dose motor fluctuations could enable a simplified drug regimen that allows physicians to individually tailor the existing levodopa daily regimen, by potentially reducing the total daily levodopa dose, increasing the dosing interval, and ultimately reducing the number of intakes, thereby maximising its benefit.

FUNDING:

BIAL.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Free-water imaging in Parkinson's disease and atypical parkinsonism

Interesting and potentially important results here... imaging markers for PD and differentiation from atypical Parkinson's is essential... replication required but very promising results...

Brain. 2015 Dec 24. pii: awv361. [Epub ahead of print]

Planetta PJ, Ofori E, Pasternak O, Burciu RG, Shukla P, DeSimone JC, Okun MS, McFarland NR, Vaillancourt DE.

http://brain.oxfordjournals.org/content/early/2015/12/23/brain.awv361

Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinson's disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinson's disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinson's disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinson's disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease group comparisons, the support vector machine 10-fold cross-validation area under the curve was between 0.93-1.00 and there was high sensitivity and specificity. The regions and diffusion measures selected by the model varied across comparisons and are consistent with pathological studies. In conclusion, the current study used a novel bi-tensor diffusion analysis model to indicate that all forms of parkinsonism had elevated free-water in the substantia nigra. Beyond the substantia nigra, both multiple system atrophy and progressive supranuclear palsy, but not Parkinson's disease, showed a broad network of elevated free-water and altered free-water corrected fractional anisotropy that included the basal ganglia, thalamus, and cerebellum. These findings may be helpful in the differential diagnosis of parkinsonian disorders, and thereby facilitate the development and assessment of targeted therapies.

Parkinson disease male-to-female ratios increase with age: French nationwide study and meta-analysis.

This is an interesting result... and will be important not only for aetiological research into PD but also predictive modelling approaches...

J Neurol Neurosurg Psychiatry. 2015 Dec 23. pii: jnnp-2015-312283. doi: 10.1136/jnnp-2015-312283. [Epub ahead of print]

Moisan F, Kab S, Mohamed F, Canonico M, Le Guern M, Quintin C, Carcaillon L, Nicolau J, Duport N, Singh-Manoux A, Boussac-Zarebska M, Elbaz A.

http://jnnp.bmj.com/content/early/2015/12/23/jnnp-2015-312283.long

BACKGROUND:

Parkinson's disease (PD) is 1.5 times more frequent in men than women. Whether age modifies this ratio is unclear. We examined whether male-to-female (M-F) ratios change with age through a French nationwide prevalence/incidence study (2010) and a meta-analysis of incidence studies.

METHODS:

We used French national drug claims databases to identify PD cases using a validated algorithm. We computed M-F prevalence/incidence ratios overall and by age using Poisson regression. Ratios were regressed on age to estimate their annual change. We identified all PD incidence studies with age/sex-specific data, and performed a meta-analysis of M-F ratios.

RESULTS:

On the basis of 149 672 prevalent (50% women) and 25 438 incident (49% women) cases, age-standardised rates were higher in men (prevalence=2.865/1000; incidence=0.490/1000 person-years) than women (prevalence=1.934/1000; incidence=0.328/1000 person-years). The overall M-F ratio was 1.48 for prevalence and 1.49 for incidence. Prevalence and incidence M-F ratios increased by 0.05 and 0.14, respectively, per 10 years of age. Incidence was similar in men and women under 50 years (M-F ratio <1.2, p>0.20), and over 1.6 (p<0.001) times higher in men than women above 80 years (p trend <0.001). A meta-analysis of 22 incidence studies (14 126 cases, 46% women) confirmed that M-F ratios increased with age (0.26 per 10 years, p trend=0.005).

CONCLUSIONS:

Age-increasing M-F ratios suggest that PD aetiology changes with age. Sex-related risk/protective factors may play a different role across the continuum of age at onset. This finding may inform aetiological PD research.

Hepatitis C virus infection as a risk factor for Parkinson disease: A nationwide cohort study

Interesting observation... I don't remember seeing this before...

Neurology. 2015 Dec 23. pii: 10.1212/WNL.0000000000002307. [Epub ahead of print]

Tsai HH, Liou HH, Muo CH, Lee CZ, Yen RF, Kao CH.

OBJECTIVE:

To determine whether hepatitis C virus (HCV) infection is a risk factor for developing Parkinson disease (PD).

METHODS:

This nationwide population-based cohort study was based on data obtained from a dataset of the Taiwan National Health Insurance Research Database for the period 2000 to 2010. A total of 49,967 patients with viral hepatitis were included for analysis. Furthermore, 199,868 people without viral hepatitis were included for comparisons. Patients with viral hepatitis were further grouped into 3 cohorts: hepatitis B virus (HBV) infection, HCV infection, and HBV-HCV coinfection. In each cohort, we calculated the incidence of developing PD. A Cox proportional hazards model was applied to estimate the risk of developing PD in terms of hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS:

The crude HRs for developing PD was 0.66 (95% CI = 0.55-0.80) for HBV infection, 2.50 (95% CI = 2.07-3.02) for HCV infection, and 1.28 (95% CI = 0.88-1.85) for HBV-HCV coinfection. The association between HCV and PD remained statistically significant after adjustments for age, sex, and comorbidities (adjusted HR = 1.29, 95% CI = 1.06-1.56).

CONCLUSIONS:

We conducted a large nationwide population-based study and found that patients with HCV exhibit a significantly increased risk of developing PD.

Mendelian Randomization - the Key to Understanding Aspects of Parkinson's Disease Causation?

Nice early christmas present to have this published today... I anticipate this approach will take us forward in understanding the causal nature of Parkinson's... particularly when it comes to the associations with some of the stranger environmental exposures for PD...

Mov Disord. 2015 Dec 23. doi: 10.1002/mds.26492. [Epub ahead of print]

Noyce AJ, Nalls MA.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26492/abstract

Parkinson's disease has multiple determinants and is associated with a wide range of exposures that appear to modify risk in traditional observational studies, including numerous lifestyle and environmental factors. Across other fields of medicine, Mendelian randomization has emerged as a powerful method to examine whether associations between exposures and disease outcomes are causal. Here we discuss the concept of Mendelian randomization, its potential relevance to Parkinson's disease, and suggest avenues through which the method could be employed to further understanding of the causal basis of Parkinson's disease.

Alpha-synuclein in gastric and colonic mucosa in Parkinson's disease: Limited role as a biomarker

Amazing how things change... 3-4 years ago there were a run of papers showing clear and definite differences in biopsies from GI tracts of patients in terms of staining for alpha-synuclein. Now there has been a run of studies showing no difference... I suspect the key lies in the final sentence of this abstract... the differences may be strain dependent... we should not give up on the gut...

Mov Disord. 2015 Dec 21. doi: 10.1002/mds.26473. [Epub ahead of print]

Chung SJ, Kim J, Lee HJ, Ryu HS, Kim K, Lee JH, Jung KW, Kim MJ, Kim MJ, Kim YJ, Yun SC, Lee JY, Hong SM, Myung SJ.

BACKGROUND:

Gastric and colonic alpha-synuclein immunoreactivity has been reported in patients with Parkinson's disease (PD). However, enteric alpha-synuclein also has been reported in healthy individuals.

OBJECTIVES:

We aimed to investigate the utility of alpha-synuclein immunoreactivity from gastric and colonic mucosal tissues obtained by routine endoscopy to detect PD, and to correlate the pathological burden of alpha-synuclein with motor and nonmotor features of PD.

METHODS:

We recruited 104 study subjects, consisting of 38 patients with PD, 13 patients with probable multiple system atrophy (MSA), and 53 healthy controls. Gastric and colonic mucosal tissues obtained by endoscopic gastroduodenoscopy and colonoscopy were assessed using alpha-synuclein immunohistochemistry. Detailed motor and nonmotor features of PD were correlated with enteric alpha-synuclein immunoreactivity.

RESULTS:

No difference was seen in the enteric α-SYN immunoreactivity among patients with PD (31.6% for stomach and 10.4% for colon), patients with MSA (40.0% for stomach and 8.0% for colon), and healthy controls (33.3% for stomach and 18.5% for colon). The frequency of positive alpha-synuclein immunoreactivity was higher in gastric biopsy tissues than in colonic biopsy tissues in all of the study groups (P < 0.05). No significant correlation was found between the presence of alpha-synuclein immunoreactivity and the motor and nonmotor features of PD.

CONCLUSIONS:

The presence of alpha-synuclein immunoreactivity in gastric and colonic mucosa was detected in a similar manner in patients with PD, patients with MSA, and controls, thus suggesting a limited role of enteric mucosal alpha-synuclein as a diagnostic biomarker for PD. Future studies are warranted to detect pathological alpha-synuclein strains.

A scan without evidence is not evidence of absence: Scans without evidence of dopaminergic deficit in a symptomatic leucine-rich repeat kinase 2 mutation carrier.

Further evidence that radio-tracer imaging can be normal despite the presence of clear motor signs perhaps due to early compensatory mechanisms...

Mov Disord. 2015 Dec 21. doi: 10.1002/mds.26450. [Epub ahead of print]

Wile DJ, Dinelle K, Vafai N, McKenzie J, Tsui JK, Schaffer P, Ding YS, Farrer M, Sossi V, Stoessl AJ.

INTRODUCTION:

The basis for SWEDD is unclear, with most cases representing PD mimics but some later developing PD with a dopaminergic deficit.

METHODS:

We studied a patient initially diagnosed with SWEDD (based on 18 F-dopa PET) who developed unequivocal PD associated with a leucine-rich repeat kinase 2 p.G2019S mutation. Repeat multitracer PET was performed at 17 years' disease duration, including (+)[11C]dihydrotetrabenazine, [11C](N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (which binds the serotonin transporter), and 18 F-dopa.

RESULTS:

The patient showed bilateral striatal dopaminergic denervation (right putamen 28% of age-matched normal, left putamen 33%). 18 F-dopa uptake was decreased, particularly on the left (mean 31% of normal vs. 45% on the more affected right side). Serotonin transporter binding was relatively preserved in the putamen (right mean 90% of normal, left 81%) and several cortical regions.

CONCLUSIONS:

SWEDD can occur in genetically determined PD and may, in some cases, be the result of compensatory nondopaminergic mechanisms operating in early disease.

Sporadic Parkinson's disease: development and distribution of α-synuclein pathology

An update on the neuropathology of sporadic PD...

Neuropathol Appl Neurobiol. 2015 Dec 13. doi: 10.1111/nan.12298. [Epub ahead of print]

Del Tredici K, Braak H.

http://onlinelibrary.wiley.com/doi/10.1111/nan.12298/abstract;jsessionid=F5CA9F77EACDD171E28C1580F36AE49F.f03t04

The development of α-synuclein-immunoreactive aggregates in selectively vulnerable neuronal types of the human central, peripheral, and enteric nervous systems is crucial for the pathogenesis of sporadic Parkinson's disease. The presence of these lesions persists into the end-phase of the disease, a process that is not subject to remission. The initial induction of α-synuclein misfolding and subsequent aggregation probably occurs in the olfactory bulb and/or the enteric nervous system. Each of these sites is exposed to potentially hostile environmental factors. Once formed, the aggregates appear to be capable of propagating transsynaptically from nerve cell to nerve cell in a virtually self-promoting pathological process. A regional distribution pattern of aggregated α-synuclein emerges that entails the involvement of only a few types of susceptible and axonally interconnected projection neurons within the human nervous system. One major route of disease progression may originate in the enteric nervous system and retrogradely reach the dorsal motor nucleus of the vagal nerve in the lower brainstem. From there, the disease process proceeds chiefly in a caudo-rostral direction through visceromotor and somatomotor brainstem centers to the midbrain, forebrain, and cerebral cortex. Spinal cord centers may become involved by means of descending projections from involved lower brainstem nuclei as well as by sympathetic projections connecting the enteric nervous system with postganglionic peripheral ganglia and preganglionic nuclei of the spinal cord. The development of experimental cellular and animal models is helping to explain the mechanisms of how abnormal α-synuclein can undergo aggregation and how transmission along axonal connectivities can occur, thereby encouraging the initiation of potential disease-modifying therapeutic strategies for sporadic Parkinson's disease.

Midlife milk consumption and substantia nigra neuron density at death

Clinico-pathological correlations between midlife milk consumption and observations made in the brains of subjects coming to post-mortem that did not have PD in life...

Neurology. 2015 Dec 9. pii: 10.1212/WNL.0000000000002254. [Epub ahead of print]

Abbott RD, Ross GW, Petrovitch H, Masaki KH, Launer LJ, Nelson JS, White LR, Tanner CM.

OBJECTIVE:

To examine the relationship between midlife milk intake and Parkinson disease (PD) incidence through associations with substantia nigra (SN) neuron density and organochlorine pesticide exposure in decedent brains from the Honolulu-Asia Aging Study.

METHODS:

Milk intake data were collected from 1965 to 1968 in 449 men aged 45-68 years with postmortem examinations from 1992 to 2004. Neuron density (count/mm2) was measured in quadrants from a transverse section of the SN. Additional measures included brain residues of heptachlor epoxide, an organochlorine pesticide found at excessively high levels in the milk supply in Hawaii in the early 1980s.

RESULTS:

Neuron density was lowest in nonsmoking decedents who consumed high amounts of milk (>16 oz/d). After removing cases of PD and dementia with Lewy bodies, adjusted neuron density in all but the dorsomedial quadrant was 41.5% lower for milk intake >16 oz/d vs intake that was less (95% confidence interval 22.7%-55.7%, p < 0.001). Among those who drank the most milk, residues of heptachlor epoxide were found in 9 of 10 brains as compared to 63.4% (26/41) for those who consumed no milk (p = 0.017). For those who were ever smokers, an association between milk intake and neuron density was absent.

CONCLUSIONS:

Milk intake is associated with SN neuron loss in decedent brains unaffected by PD. Whether contamination of milk with organochlorine pesticides has a role in SN neurodegeneration warrants further study.